Tetrahydropyridopyrazines modulators of gpr6

ABSTRACT

which are useful as modulators of GPR6, pharmaceutical compositions thereof, methods for treatment of conditions associated with GPR6, processes for making the compounds and intermediates thereof.

FIELD OF THE INVENTION

The present invention relates to medicinal chemistry, pharmacology, andmedicine.

BACKGROUND OF THE INVENTION

The present invention provides compounds that are G-Protein-CoupledReceptor 6 (hereinafter referred to as GPR6) modulators. GPR6 is GPCRthat signals via the Gs pathway. GPR6 receptors are highly expression inthe central nervous system (CNS), particularly medium spiny neurons(MSNs) of the striatum, with minimal expression in peripheral tissues.The major striatal targets of dopaminergic innervation reside in themedium spiny neurons (MSNs) of the striatopallidal (indirect) andstriatonigral (direct) output pathways. The MSNs of the direct outputpathway express D1 dopamine receptors whereas those in the indirectpathway express D2 receptors. GPR6 is enriched in D2 receptor expressingMSNs in the striatum where GPR6 activity is functionally opposed to D2receptor signaling. Antagonism or inverse agonism of Gs coupled GPR6decreases cAMP in MSNs and provides a functional alternative to dopaminemediated activation of D2 receptors. Therefore, the compounds of thepresent invention are useful to treat a variety of neurological andpsychiatric disorders, including Parkinson's disease.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein

-   R₁ is selected from the group consisting of optionally substituted    C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocyclyl,    optionally substituted C₆₋₁₀ aryl, and optionally substituted C₁₋₁₀    heteroaryl;-   X₁ is N and X₂ is CH; or-   X₁ is CH and X₂ is N; or-   X₁ is N and X₂ is N;-   when X₁ is N, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —C(O)—, and —S(O)₂—;-   when X₁ is CH, Z is selected from the group consisting of C₁₋₆    alkylene, C₁₋₆ haloalkylene, —O—, —C(O)—, —NH—, —S—, —S(O)—, and    —S(O)₂—;-   q is 0, 1, or 2;-   s is 0, 1, or 2;-   R₂ is —OR₅ or —NR₆R₇;-   R₃, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and trifluoromethyl;-   p is 0, 1, or 2;-   R₄, each time taken, is independently selected from the group    consisting of C₁₋₆ alkyl, hydroxy, and halo;-   r is 0 or 1;-   R₅ is selected from the group consisting of C₁₋₆ alkyl and C₃₋₈    cycloalkyl;-   R₆ is selected from the group consisting of hydrogen and C₁₋₆ alkyl;-   R₇ is selected from the group consisting of optionally substituted    C₁₋₆ alkyl, C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,    optionally substituted C₁₋₁₀ heteroaryl, and optionally substituted    C₃₋₆ heterocyclyl;-   X₃ is CCH₃ and X₄ is N; or-   X₃ is N and X₄ is CCH₃;-   excluding the compounds:    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine,    N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine,    (1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone,    N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    (S)—N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine,    1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one,    (R)-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    (R)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    (S)—N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine,    5-chloro-1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one,    N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine,    and    N-cyclopropyl-3-(1-(2,4-difluorobenzyl)piperidin-4-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;-   or a pharmaceutically acceptable salt thereof.

The present invention also provides pharmaceutical compositions,comprising: a compound of formula I or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable excipient.

The compounds of the present invention are modulators of GPR6 and areuseful to treat a variety of neurological and psychiatric disorders, forexample movement disorders including Parkinson's disease, levodopainduced dyskinesias, and Huntington's disease, drug addiction, eatingdisorders, cognitive disorders, schizophrenia, bipolar disorders, anddepression. Thus, the present invention also provides methods oftreating the conditions associated with GPR6 described hereincomprising, administering to a patient in need thereof an effectiveamount of the compounds of the invention. The present invention providesfor the use of the compounds of the invention as a medicament, includingfor treatment of the conditions associated with GPR6 described herein,and including for the manufacture of a medicament for treating theconditions associated with GPR6 described herein.

The present invention also provides processes from making GPR6modulators and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “C₁₋₄ alkyl” refers to a straight or branched alkyl chain ofone to four carbon atoms.

The term “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄ alkyloptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of optionally substituted C₁₋₄ alkoxy, C₁₋₄thioalkoxy, C₁₋₉ amide, C₁₋₇ amido, amino, C₁₋₈ alkylamino, C₁₋₅oxycarbonyl, C₁₋₅ carbonyloxy, C₁₋₈ sulfonyl, cyano, optionallysubstituted C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy, nitro,oxo, optionally substituted C₃₋₆ heterocyclyl, optionally substitutedC₁₋₁₀ heteroaryl, and optionally substituted C₆₋₁₀ aryl.

More particularly “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄alkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, C₃₋₆ heterocyclyl optionally substituted on any ring nitrogenby C₁₋₄ alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

Even more particularly “optionally substituted C₁₋₄ alkyl” refers to aC₁₋₄ alkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, C₃₋₆ heterocyclyl optionally substituted onany ring nitrogen by C₁₋₄ alkyl, and optionally substituted phenyl.

The term “C₁₋₆ alkyl” refers to a straight or branched alkyl chain ofone to six carbon atoms.

The term “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆ alkyloptionally substituted with 1 to 7 substituents independently selectedfrom the group consisting of amino, C₁₋₈ alkylamino, optionallysubstituted C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅oxycarbonyl, C₁₋₅ carbonyloxy, C₁₋₈ sulfonyl, cyano, optionallysubstituted C₃₋₈ cycloalkyl, halo, hydroxy, oxo, optionally substitutedC₁₋₁₀ heteroaryl, optionally substituted C₃₋₆ heterocyclyl, andoptionally substituted C₆₋₁₀ aryl.

More particularly “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆alkyl optionally substituted with 1 to 7 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, C₃₋₆ heterocyclyl optionally substituted on any ring nitrogenby C₁₋₄ alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

Even more particularly “optionally substituted C₁₋₆ alkyl” refers to aC₁₋₆ alkyl optionally substituted with 1 to 7 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, C₃₋₆ heterocyclyl optionally substituted onany ring nitrogen by C₁₋₄ alkyl, and optionally substituted phenyl.

The term “C₁₋₆ haloalkyl” refers to a straight or branched alkyl chainof one to six carbon atoms substituted with 1 to 3 halogen atoms. Moreparticularly, the term “C₁₋₆ haloalkyl” refers fluoromethyl anddifluoromethyl.

The term “C₁₋₈ sulfonyl” refers to a sulfonyl linked to a C₁₋₆ alkylgroup, C₃₋₈ cycloalkyl, or an optionally substituted phenyl.

The term “C₁₋₆ alkylene” refers to a straight or branched, divalent,alkylene chain of one to six carbon atoms.

The term “C₁₋₆ haloalkylene” refers to a straight or branched, divalent,alkylene chain of one to six carbon atoms substituted with 1 to 3halogen atoms. More particularly, the term “C₁₋₆ haloalkylene” refersfluoromethylene and difluoromethylene.

The term “C₁₋₄ alkoxy” refers to a C₁₋₄ alkyl attached through an oxygenatom.

The term “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄ alkoxyoptionally substituted with 1 to 6 substituents independently selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,cyano, optionally substituted C₃₋₈ cycloalkyl, halo, hydroxy, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted C₆₋₁₀ aryl.While it is understood that where the optional substituent is C₁₋₄alkoxy or hydroxy then the substituent is generally not alpha to thealkoxy attachment point, the term “optionally substituted C₁₋₄ alkoxy”includes stable moieties and specifically includes trifluoromethoxy,difluoromethoxy, and fluoromethoxy.

More particularly “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄alkoxy optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈cycloalkyl, halo, hydroxy, and optionally substituted phenyl. Even moreparticularly “optionally substituted C₁₋₄ alkoxy” refers totrifluoromethoxy, difluoromethoxy, and fluoromethoxy.

The term “C₁₋₉ amide” refers to a —C(O)NR_(a)R_(b) group in which R_(a)is selected from the group consisting of hydrogen and C₁₋₄ alkyl, andR_(b) is selected from the group consisting of hydrogen, C₁₋₃ alkyl, andoptionally substituted phenyl.

The term “C₁₋₇ amido” refers to a —NHC(O)R, group in which R_(a) isselected from the group consisting of hydrogen, C₁₋₆ alkyl, andoptionally substituted phenyl.

The term “C₁₋₅ carbamoyl” refers to an O- or N-linked carbamatesubstituted with a terminal C₁₋₄ alkyl.

The term “C₁₋₅ ureido” refers to a urea optionally substituted with aC₁₋₄ alkyl.

The term “C₁₋₈ alkylamino” refers to a —NR_(d)R_(e) group in which R_(d)is a C₁₋₄ alkyl and R_(e) is selected from the group consisting ofhydrogen and C₁₋₄ alkyl.

The term “C₆₋₁₀ aryl” refers to a monocyclic and polycyclic unsaturated,conjugated hydrocarbon having five to ten carbon atoms, and includesphenyl, and naphthyl.

More particularly “C₆₋₁₀ aryl” refers to phenyl.

The term “optionally substituted C₆₋₁₀ aryl” refers to a C₆₋₁₀ aryloptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of optionally substituted C₁₋₄ alkyl,optionally substituted C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅ oxycarbonyl, C₁₋₅ carbonyloxy,C₁₋₈ sulfonyl, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, aminosulfonyl, C₁₋₁₀aminosulfonyl, C₁₋₅ ureido, cyano, halo, and hydroxyl.

More particularly “optionally substituted C₆₋₁₀ aryl” refers to a C₆₋₁₀aryl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, hydroxy, amino, trifluoromethyl, and trifluoromethoxy.

Even more particularly “optionally substituted C₆₋₁₀ aryl” refers tophenyl optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, trifluoromethyl, and trifluoromethoxy.

The term “C₁₋₅ oxycarbonyl” refers to an oxycarbonyl group (—CO₂H) andC₁₋₄ alkyl ester thereof.

The term “C₁₋₅ carbonyloxy” refers to a carbonyloxy group (—O₂CR_(f)),in which R_(f) is selected from the group consisting of hydrogen andC₁₋₄ alkyl, for example, acetoxy.

The term “C₃₋₈ cycloalkyl” refers to monocyclic or bicyclic, saturatedor partially (but not fully) unsaturated alkyl ring of three to eightcarbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. It is understood that the term includesbenzofused cyclopentyl and cyclohexyl.

The term “optionally substituted C₃₋₈ cycloalkyl” refers to a C₃₋₈cycloalkyl optionally substituted with 1 to 6 substituents independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,optionally substituted C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₇ amido, amino, C₁₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy,halo, hydroxy, nitro, oxo, optionally substituted C₁₋₁₀ heteroaryl, andoptionally substituted phenyl.

More particularly “optionally substituted C₃₋₈ cycloalkyl” refers to aC₃₋₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of C₁₋₄ alkoxy, halo,hydroxy, and C₁₋₄ alkyl optionally substituted with C₁₋₄ alkoxy, halo,and hydroxy.

The term “C₃₋₈ cycloalkoxy” refers to a C₃₋₈ cycloalkyl attached throughand oxygen.

The terms “halogen” and “halo” refers to a chloro, fluoro, bromo or iodoatom.

The term “C₃₋₆ heterocyclyl” refers to a 4 to 8 membered monocyclic orbicyclic, saturated or partially (but not fully) unsaturated ring havingone or two heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur and the ring optionally includes a carbonyl to form alactam or lactone. It is understood that where sulfur is included thatthe sulfur may be either —S—, —SO—, and —SO₂—. It is also under that theterm includes spirofused bicyclic systems. For example, but notlimiting, the term includes azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl,hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and thelike. It is understood that a C₃₋₆ heterocyclyl can be attached as asubstituent through a ring carbon or a ring nitrogen atom.

More particularly “C₃₋₆ heterocyclyl” is selected from the groupconsisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, andtetrahydrofuryl.

The term “optionally substituted C₃₋₆ heterocyclyl” refers to a C₃₋₆heterocyclyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting ofoptionally substituted C₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy,C₁₋₉ amide, C₁₋₇ amido, amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano,optionally substituted C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy,nitro, oxo, and optionally substituted phenyl; and optionallysubstituted on any ring nitrogen with a substituent independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocyclyl, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

More particularly “optionally substituted C₃₋₆ heterocyclyl” refers to aC₃₋₆ heterocyclyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, halo, and hydroxy and optionally substituted on anyring nitrogen with a C₁₋₄ alkyl.

The term “C₁₋₁₀ heteroaryl” refers to a five to thirteen membered,monocyclic or polycyclic fully unsaturated, ring or ring system with oneto ten carbon atoms and one or more, typically one to four, heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur. Forexample, but not limiting, the term includes furyl, thienyl, pyrrolyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidyl, azepinyl, diazepinyl, benzazepinyl, benzodiazepinyl,benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl,benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl,benzopyrazinyl, benzopyrazolyl, imidazopyridyl, pyrazolopyridyl,pyrrolopyridyl, quinazolyl, thienopyridyl, imidazopyridyl, quinolyl,isoquinolyl benzothiazolyl, and the like. It is understood that a C₁₋₁₀heteroaryl can be attached as a substituent through a ring carbon or aring nitrogen atom where such an attachment mode is available, forexample for a pyrrolyl, indolyl, imidazolyl, pyrazolyl, azepinyl,triazolyl, pyrazinyl, etc.

More particularly “C₁₋₁₀ heteroaryl” is selected from the groupconsisting of furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,pyrazolyl, triazolyl, pyridyl, and pyrimidyl.

The term “optionally substituted C₁₋₁₀ heteroaryl” refers to a C₁₋₁₀heteroaryl optionally substituted with 1 to 5 substituents on carbonindependently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₇ amido, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido,aminosulfonyl, C₁₋₁₀ aminosulfonyl,C₁₋₅ ureido, optionally substitutedC₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, cyano, halo, hydroxyl,oxo, nitro, C₁₋₅ carbonyloxy, C₁₋₅ oxycarbonyl, and C₁₋₈ sulfonyl andoptionally substituted with a substituent on each nitrogen independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₁₋₈ sulfonyl, optionally substituted C₃₋₆ heterocyclyl, and optionallysubstituted phenyl.

More particularly “optionally substituted C₁₋₁₀ heteroaryl” refers to aC₁₋₁₀ heteroaryl optionally substituted with 1 to 3 substituents oncarbon independently selected from the group consisting of amino, C₁₋₈alkylamino, C₁₋₉ amide, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo, hydroxyl,oxo, trifluoromethyl, and trifluoromethoxy and optionally substituted ona ring nitrogen with a C₁₋₄ alkyl.

Even more particularly “optionally substituted C₁₋₁₀ heteroaryl” refersto a C₁₋₁₀ heteroaryl selected from the group consisting of furyl,thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, diazolyl,pyridyl, pyrimidyl, and triazolyl each optionally substituted with 1 to3 substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, cyano, halo, trifluoromethyl, and trifluoromethoxyand optionally substituted on a ring nitrogen with a methyl.

The term “oxo” refers to an oxygen atom doubly bonded to the carbon towhich it is attached to form the carbonyl of a ketone or aldehyde. Forexample, a pryidone radical is contemplated as an oxo substituted C₁₋₁₀heteroaryl.

The term “optionally substituted phenyl” refers to a phenyl groupoptionally substituted with 1 to 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₆ amide, amino,C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro, C₁₋₈sulfonyl, and trifluoromethyl.

More particularly “optionally substituted phenyl” refers to a phenylgroup optionally substituted with 1 to 5 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉amino, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro,and trifluoromethyl.

The term “C₁₋₆ sulfonylamido” refers to a —NHS(O)₂—R_(g) group whereinR_(g) is selected from the group consisting of C₁₋₆ alkyl and optionallysubstituted phenyl.

The term “aminosulfonyl” refers to a —S(O)₂NH₂.

The term “C₁₋₁₀ aminosulfonyl” refers to a —S(O)₂NR_(h)R_(i) groupwherein R_(h) is selected from the group consisting of hydrogen and C₁₋₄alkyl and R_(i) is selected from the group consisting of C₁₋₄ alkyl, andoptionally substituted phenyl.

The term “C₁₋₄ thioalkoxy” refers to a C₁₋₄ alkyl attached through asulfur atom.

The term “pharmaceutically acceptable salt” refers to salts ofpharmaceutically acceptable organic acids and bases or inorganic acidsand bases. Such salts are well known in the art and include thosedescribed in Journal of Pharmaceutical Science, 66, 2-19 (1977). Anexample is the hydrochloride salt.

The term “substituted,” including when used in “optionally substituted”refers to one or more hydrogen radicals of a group are replaced withnon-hydrogen radicals (substituent(s)). It is understood that thesubstituents may be either the same or different at every substitutedposition. Combinations of groups and substituents envisioned by thisinvention are those that are stable or chemically feasible.

The term “stable” refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production. In anon-limiting example, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for about a week.

It is understood that, where the terms defined herein mention a numberof carbon atoms, the mentioned number refers to the mentioned group anddoes not include any carbons that may be present in any optionalsubstituent(s) thereon.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as isomers. All stereoisomers of the compoundsof the invention, including geometric isomers, enantiomers, anddiastereomers, in any ratio, are contemplated to be within the scope ofthe present invention.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as tautomers. All tautomeric forms the compoundsof the invention are contemplated to be within the scope of the presentinvention.

Compounds of the invention also include all pharmaceutically acceptableisotopic variations, in which at least one atom is replaced by an atomhaving the same atomic number, but an atomic mass different from thepredominant atomic mass. Isotopes suitable for inclusion in compounds offormula I include radioactive isotopes.

The terms “compounds of the invention” and “a compound of the invention”and “compounds of the present invention, and the like include theembodiment of formula I and the other more particular embodimentsencompassed by formula I described herein and exemplified compoundsdescribed herein and a pharmaceutically acceptable salt of each of theseembodiments.

(a) One embodiment relates to compounds of formula I wherein X₁ is CHand X₂ is N.

(b) One embodiment relates to compounds of formula I wherein X₁ is N andX₂ is N.

(c) One embodiment relates to compounds of formula I and embodiment (a)and (b) wherein X₃ is CCH₃ and X₄ is N.

(d) One embodiment relates to compounds of formula I and embodiment (a)and (b) wherein X₃ is N and X₄ is CCH₃.

(e) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), and (d) wherein R₁ is optionally substituted C₆₋₁₀ aryl.

(f) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), and (e) wherein Z is C₁₋₆ alkylene.

(g) One embodiment relates to compounds formula I and embodiments (a),(b), (c), (d), and (e) wherein Z is C₁₋₆ haloalkylene.

(h) One embodiment relates to compounds formula I and embodiments (a),(c), (d), and (e) wherein Z is —O—.

(i) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), and (e)wherein Z is —C(O)—.

(j) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), and (i) wherein R₂—NR₆R₇. Inanother embodiment within embodiment (j), R₆ is hydrogen and R₇ is C₁₋₆alkyl. In yet another embodiment within embodiment (j), R₆ is hydrogenand R₇ is C₃₋₈ cycloalkyl. In yet another embodiment within embodiment(j), R₆ is hydrogen and R₇ is C₃₋₆ heterocyclyl.

(k) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), and (j) wherein s is 1.

(l) One embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), and (k) wherein q is1.

(ay) Another embodiment relates to a pharmaceutically acceptable salt ofeach of the above embodiments.

(az) Another embodiment relates to a pharmaceutically acceptable salt ofeach of the exemplified compounds.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. The products of eachstep can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups tominimize unwanted reactions. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991). In the schemes belowstarting materials are either commercially available or can be readyprepared by methods well known in the art.

Scheme A depicts the formation of compounds in which X₂ is N.

In Scheme A, step 1, an appropriate compound of formula 1 is contactedwith an appropriate compound of formula 2 to give a compound of formula3. An appropriate compound of formula 1 is one in which Hal is a halogenand R₄ and r are as desired in the final compound of formula I. Anappropriate compound of formula 2 is one in which R₁, Z, R₃, p, s, and qare as desired in the final compound of formula I or give rise to R₁, Z,and R₃ as desired in the final compound of formula I. Compounds offormula 2 are either commercially available or they can be readilyprepared by methods well known in the art. For example, compounds offormula 2 where Z is oxygen can be prepared by Mitsunobu reactionbetween a piperidinol and an aryl alcohol.

The reaction is carried out in a suitable organic solvent like dioxane,n-butanol, dimethyl sulfoxide and the like with or without base such asdiisopropylethylamine and triethylamine. The reaction is generallycarried out at a temperature of from 0 to 80° C.

It is understood that a compound of formula 1 can also be treated withpiperazine to give rise to compounds in which X₁ is N. The piperazinederivative can be further modified by reductive amination, alkylation,arylation, amidation, sulfonylation and the like to provide a compoundof formula 3. Also the piperazine can be protected and elaborated asmentioned above after deprotection in a later step if desired.

In Scheme A, step 2, a compound of formula 3 is contacted with anappropriate compound of formula 4 to give a compound of formula I. Anappropriate compound of formula 4 is HOR₅ or HNR₆R₇ in which R₅ or R₆and R₇ are as desired in the final compound of formula I.

Where the compound of formula 4 is an amine, HNR₆R₇, the reaction iscarried out in a suitable organic solvent like dioxane, ethanol,tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and the like,with or without a base such as sodium hydroxide, diisopropylethylamineor triethylamine. The reaction is generally carried out at temperaturebetween 20 to 150° C.

Where the compound of formula 4 is an alcohol, HOR₅, the reaction iscarried out in a suitable organic solvent like dioxane, tetrahydrofuran,dimethyl sulfoxide, N,N-dimethylformamide and the like, with a base suchas sodium hydride, lithium hydride, potassium t-butoxide, and the like.The reaction is generally carried out at temperature between 0 to 150°C.

Alternatively, as depicted in Scheme A, step 3, using the methodologydescribed above, an appropriate compound of formula 1 can be contactedwith an appropriate compound of formula 2 to give a compound of formula5.

As depicted in Scheme A, step 4, a compound of formula 5 can becontacted with a compound of formula 2 to give a compound of formula I.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme A may be varied to provide compounds of formula I. Inparticular, the order of the steps required to produce the compounds offormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Other variations are possible and are readily understood bythe skilled person.

Scheme B depicts the formation of compounds in which X₂ is CH.

In Scheme B, step 1, an appropriate compound of formula 1, as describedabove, is contacted with an appropriate compound of formula 6 to give acompound of formula 7. An appropriate compound of formula 6 is one inwhich R₁, Z, R₃, p, s, and q are as desired in the final compound offormula I or give rise to R₁, Z, and R₃ as desired in the final compoundof formula I and Y a boronic acid or boronic ester. It is alsounderstood that the group depicted as R₁—Z— can be replaced by anappropriate protecting group, such a methyl, benzyl, t-BOC, or Cbz,subsequent removal of the protecting group and installation of R₁—Z— asdesired in the final product of formula I.

Such reactions are generally known as a Suzuki reaction and are wellknown in the art. While a Suzuki reaction is depicted in Scheme B it isunderstood that other carbon-carbon bond forming coupling reactions canbe used with compounds of formula 6 having Y other than boronic acid oresters to produce compounds of formula I.

In Scheme B, step 2, a compound of formula 7 is contacted with anappropriate compound of formula 4 to give a compound of formula 8. Anappropriate compound of formula 4 and general reaction conditions aredescribed above in Scheme A, step 2.

Alternately, Scheme B, step 3, depicts Suzuki reaction with anappropriate compound of formula 6 and an appropriate compound of formula5 as described above to give a compound of formula 8.

In Scheme B, step 4, a compound of formula 8 is reduced to a compound offormula I. Such reductions are well known in the art. The reaction iscarried out in a suitable organic solvent like dioxane, ethanol,methanol, isopropanol, tetrahydrofuran, and the like. The reaction isgenerally carried out using hydrogen and a catalyst, such as platinum orpalladium catalyst.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme B may be varied to provide compounds of formula I. Inparticular, the order of the steps required to produce the compounds offormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties.

It is also understood that some compounds of formula I may be elaboratedto other compounds of formula I, in an additional steps not shown.Compounds of formula I may be elaborated in a variety of ways. Suchreactions include hydrolysis, oxidation, reduction, alkylation,amidations, and the like. Also, in an optional step, not shown in theschemes above, the compounds of formula I can be converted topharmaceutically acceptable salts by methods well known and appreciatedin the art.

The following examples are intended to be illustrative and non-limiting,and represent specific embodiments of the present invention.

Proton nuclear magnetic resonance (NMR) spectra were obtained for manyof the compounds in the following examples. Characteristic chemicalshifts (δ) are given in parts-per-million downfield fromtetramethylsilane using conventional abbreviations for designation ofmajor peaks, including s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), and br (broad). Other abbreviations have theirusual meaning unless otherwise indicated. The mass spectra, unlessotherwise indicated, were recorded using either electrospray ionization(ESI) or atmospheric pressure chemical ionization.

The examples below were carried out in appropriate vessels and weretypically stirred. Where indicated, products of certain preparations andexamples are purified by HPLC. Where indicated products of thepreparations and examples were purified by HPLC.

HPLC Method A: Pump: Shimadzu LC-8A; UV/Vis: SPD-20A; Software:LCSolution. A Phenomenex Gemini® C18, 5 μm, ID 30×100 mm column was usedand eluted with gradients of ACN (containing 0.035% TFA) and water(containing 0.005% TFA). A 10% to 100% ACN gradient was used unlessotherwise indicated.

HPLC Method B: Pump: Waters 2525 or 2545; MS: ZQ; Software: MassLynx. AXbridge™ C18, 5 μm, ID 30×75 mm column was used and eluted withgradients of 10 mMol NH4HCO3 in water/acetonitrile (pH=9.5-10).

After isolation by chromatography, the solvent is removed and theproduct is obtained by evaporating product containing fractions (e.g.,GeneVac™), rotary evaporator, evacuated flask, lyophilization, etc.

The abbreviations used throughout have their conventional meaningsunless indicated otherwise. For example, the following abbreviations areused: ACN (acetonitrile); aq (aqueous); Boc or t-BOC(tert-butoxycarbonyl); Cbz (carbobenzyloxy); DCM (dichloromethane); DMSO(dimethyl sulfoxide); TFA (trifluoroacetic acid); HOAc (acetic acid),MeOH (methanol), PE (petroleum ether), EA or EtOAc (ethyl acetate) andthe like.

Preparation 1 (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone

A solution of 2-bromo-4-chloro-1-fluorobenzene (175 μL, 1.377 mmol) inTHF (4.59 mL) at −78° C. was treated with n-BuLi (2.6 M, 741 μL, 1.928mmol) and the reaction mixture was stirred for 30 min. To this was addedtert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 mg,0.918 mmol) in one portion. The cooling bath was removed and theresulting reaction mixture was allowed to warm to rt and stirred for 1.5h. Purification by automated flash silica gel chromatography using 10%EtOAc in hexanes afforded tert-butyl4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 92%) asa yellow oil. ESI-MS m/z [M+Na]+ 364.20.

A solution of tert-butyl4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 0.843mmol) in dioxane (2.41 mL) was treated with HCl (2.11 mL, 8.43 mmol) atrt and the resulting reaction mixture was stirred overnight. Thereaction mixture was diluted with hexanes and filtered by suction toafford (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone as its HClsalt (146 mg, 62.3%) as a yellow solid. ESI-MS m/z [M+H]+ 242.20.

Preparation 2 4-(2,4-difluorophenoxy)piperidine

To a solution of 2,4-difluorophenol (10 g, 77 mmol), PPh3 (30.2 g, 115mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (30.9 g, 154mmol) in THF (400 mL) was added DEAD (18.3 mL, 115 mmol) at 0° C.dropwise. After the addition was completed, the resulting mixture wasallowed to stir at 40° C. for 16 h. The mixture was poured into waterand extracted with EtOAc (3×400 mL). The combined organic layers weredried over Na2SO4, filtered and concentrated to give the crude product.Purification by flash silica gel chromatography, eluting with 80:1 PE:EtOAc, gave tert-butyl 4-(2,4-difluorophenoxy)piperidine-1-carboxylateas an oil (20 g, 83%).

A solution of tert-butyl 4-(2,4-difluorophenoxy)piperidine-1-carboxylate(20 g, 63.8 mmol) in 4:1 HCl/EtOAc (250 mL) was stirred at 25° C. for 1h. The mixture was concentrated to give the title compound, as its HClsalt, as a white solid (15.4 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm1.84 (m, 2H), 2.08 (m, 2H), 3.05 (m, 2H), 3.20 (m, 2H), 4.57 (m, 1H),7.04 (m, 1H), 7.31 (m, 2H), 8.95 (br d, 2H).

Preparation 3 3-fluoro-4-(piperidin-4-yloxy)benzonitrile

A solution of 3,4-difluorobenzonitrile (28 g, 201 mmol) and tert-butyl4-hydroxypiperidine-1-carboxylate (40.5 g, 201 mmol) in THF (500 mL) wastreated with sodium hydride (4 g, 100 mmoL) and stirred at 25° C. for 16h. The reaction mixture was washed with water, extracted with EtOAc, andthe crude product purified by flash silica gel chromatography gavetert-butyl 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (25 g,39%).

A solution of tert-butyl4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylate (42 g, 131 mmol)dissolved in 4:1 HCl/EtOAc (100 mL) was stirred for 5 h. The mixture wasconcentrated to give the title compound as its HCl salt (12 g, 36%). 1HNMR (400 MHz, DMSO-d6) δ ppm 1.89 (m, 2H), 2.14 (m, 2H); 3.08 (m, 2H),3.21 (m, 2H), 4.86 (m, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz,1H), 7.89 (m, 1H); ESI-MS m/z [M+H]+ 220.7.

Preparation 4 4-((2,4-difluorophenyl)fluoromethyl)piperidine

To a 0° C. solution of tert-butyl4-(2,4-difluorobenzoyl)piperidine-1-carboxylate (1.28 g, 3.93 mmol) inMeOH (15.7 mL) was added NaBH₄ (0.372 g, 9.84 mmol). The ice bath wasremoved and the reaction mixture stirred for 2 h at room temperaturethen was quenched with saturated aqueous NH4Cl. The organic layer wasextracted with EtOAc, washed with water and dried over MgSO4. Thesolvent was removed under reduced pressure gave tert-butyl4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate as awhite hygroscopic solid.

To a 78° C. solution of tert-butyl4-((2,4-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (200 mg,0.611 mmol) in DCM (3.055 mL) was added DAST (242 μL, 1.833 mmol). Themixture was stirred at −78° C. for 30 min, then quenched with MeOH.Flash silica gel chromatography using a gradient of 0% to 100% EtOAc inhexanes gave tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate as acolorless oil.

To a solution of racemic tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (148 mg,0.449 mmol) in dioxane (1.50 mL) was added HCl (4 M in dioxane, 337 μL,1.348 mmol). The mixture was heated at 45° C. for 16 h then concentratedin vacuo to give the title compound as its HCl salt (109 mg, 91%) as awhite solid.

Preparation 5 (R)-4-((2,4-difluorophenyl)fluoromethyl)piperidine

tert-Butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylatewas subjected to chiral SFC separation to give (R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate.(R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (2.8 g,8.50 mmol) was dissolved in EtOAc (20 mL) and HCl (4 M in EtOAc, 21 mL)was added. The reaction mixture was stirred at 23° C. for 2 h.Evaporation of the solvent gave the title compound as its HCl salt (2.1g, 93%). ESI-MS m/z [M+H]+ 229.9.

Preparation 6 (S)-4-((2,4-difluorophenyl)fluoromethyl)piperidine

tert-Butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylateas

was subjected to chiral SFC separation to give (R)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate. The HClsalt of the title compound was prepared in similar fashion toPreparation 5, using (S)-tert-butyl4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate. ESI-MS m/z[M+H]+ 229.9.

Preparation 7 4-((2-fluorophenyl)sulfonyl)piperidine

A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), andK2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C.overnight. The reaction mixture was poured into water and extractedtwice with EtOAc. The combined organics were dried over sodium sulfate,filtered, and concentrated under reduced pressure gave tert-butyl4-((2-fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98g, 98%), which was carried forward without purification.

A solution of tert-butyl4-((2-fluorophenyl)thio)piperidine-1-carboxylate (1.98 g, 6.36 mmol) inTHF (54.5 mL) and MeOH (18.2 mL) at 0° C. was treated with a coldsolution of Oxone® (9.77 g, 15.9 mmol) in water (54.5 mL). The reactionmixture was stirred for 5 h, gradually warming to room temperature. Thereaction mixture was poured into water and extracted twice with EtOAc.The combined organics were washed with water and then saturated aqueousNaCl, dried over Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by flash silica gel chromatographyusing a gradient of 10% to 50% EtOAc with 0.1% triethylamine in heptanesgave tert-butyl 4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate asa pale yellow oil (1.31 g, 60%).

A solution of tert-butyl4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.31 g, 3.82 mmol)in dioxane (12.7 mL) at room temperature was treated with 4M HCl indioxane (9.55 ml, 38.2 mmol). The reaction mixture was allowed to stirat room temperature overnight. The reaction mixture was concentratedunder reduced pressure. The resulting white solid was triturated withhexanes, filtered, collected, and lyophilized overnight to give thetitle compound, as its HCl salt, as a white solid (815.1 mg, 76%).ESI-MS m/z [M+H]+ 243.95.

Preparation 8 4-((2-fluoro-4-methoxyphenyl)sulfonyl)piperidine

A mixture of 2,4-difluorobenzenethiol (0.810 mL, 7.15 mmol), tert-butyl4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), andK2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C.overnight. The reaction mixture was poured into water and extractedtwice with EtOAc. The organic layer was dried over Na2SO4, filtered, andconcentrated under reduced pressure to afford tert-butyl4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as ayellow oil, which was carried forward without purification.

A solution of tert-butyl4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g, 6.50mmol) in THF/MeOH (3:1, 74 mL) at 0° C. was treated with a cold solutionof Oxone® (9.99 g, 16.25 mmol) in water (56 mL). The reaction mixturewas allowed to stir overnight, gradually warming to room temperature.The reaction mixture was poured into water and extracted twice withEtOAc. The combined organics were washed with water and then saturatedaqueous NaCl, dried over Na2SO4, filtered, and concentrated underreduced pressure. The residue was purified by flash silica gelchromatography using a gradient of 10% to 40% EtOAc with 0.1%triethylamine in heptanes gave tert-butyl4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (1.32 g, 56%)as a white solid. ESI-MS m/z [M+Na]+ 383.80.

To a suspension of tert-butyl4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (50 mg, 0.138mmol) in MeOH (461 μL) was added sodium methoxide (25.6 μL, 0.138 mmol,5.4 M in MeOH) dropwise. The reaction mixture was allowed to stir at 45°C. for 20 min then concentrated in vacuo. Boc deprotection was carriedout by addition of HCl (138 μL, 0.553 mmol, 4 M in dioxane) to the crudereaction mixture in 300 μL dioxane. Stirring at 50° C. for 24 h followedby concentration in vacuo yielded the title compound as its HCl salt (57mg) as a white solid (10:1 regioisomeric mixture). ESI-MS m/z [M+H]+274.00.

Preparation 9 4-((3-fluorophenyl)sulfonyl)piperidine

A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(1.0 g, 3.58 mmol), K2CO3 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol(0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23° C. for 5 min.The reaction mixture was stirred at 80° C. for 17 h, cooled to 23° C.and partitioned between EtOAc and water. The layers were separated, theorganic phase was washed with brine, dried over Na2SO4, filtered, rinsedwith EtOAc, and dried in vacuo gave tert-butyl4-((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 100%) as ayellow oil. ESI-MS m/z [M+H]+ 255.9.

A mixture of basic alumina (3.0 g, 29.4 mmol) in water (0.6 mL) wasstirred at 23° C. for 5 min. Next, ACN (12 mL) was added followed by asolution of tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate(1.115 g, 3.58 mmol) in CHCl3 (8 mL). Next, Oxone® (6.60 g, 10.74 mmol)was added and the reaction mixture was stirred at 60° C. for 19 h. Thereaction mixture was cooled to 23° C., filtered, rinsed with CHCl3, andthe filtrate was washed with water (10 mL). The organic layer was driedover Na2SO4, filtered, rinsed with CHCl3, and dried in vacuo. The cruderesidue was dissolved in toluene (5 mL) and purified via medium pressurechromatography using a gradient of 10% to 100% EtOAc with 0.1%triethylamine in heptane on a 80 g silica gel column (Single Step™) gavetert-butyl 4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (0.769g, 62.5%) as a white solid. ESI-MS m/z [M+Na]+ 365.9.

To a solution of tert-butyl4-((3-fluorophenyl)sulfonyl)piperidine-1-carboxylate (756 mg, 2.201mmol) in dioxane (5.0 mL) was added HCl (4 M in dioxane, 5.50 mL, 22.01mmol) at 23° C. The reaction was stirred at 23° C. for 21 h to furnish awhite suspension. The resulting solid was filtered, rinsed with dioxaneand dried in vacuo to give the title compound as its HCl salt (582.6 mg,95%) as a white solid. ESI-MS m/z [M+H]+ 243.9.

Preparation 10 4-((3-methoxyphenyl)sulfonyl)piperidine

The title compound as its HCl salt was prepared in a similar manner toPreparation 9, with the exception that additional chloroform was used inplace of ACN in the second step. ESI-MS m/z [M+H]+ 255.9.

Preparation 11 4-((4-fluorophenyl)sulfonyl)piperidine

A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(1.42 g, 5.08 mmol), 4-fluorobenzenethiol (0.663 ml, 6.10 mmol) andK2CO3 (1.054 g, 7.62 mmol) in ACN (12.71 mL) was stirred at 85° C.overnight. The reaction mixture was filtered by suction and the solventremoved gave tert-butyl 4-((4-fluorophenyl)thio)piperidine-1-carboxylate(1.5 g, 95%) as a white solid.

A solution of tert-butyl4-((4-fluorophenyl)thio)piperidine-1-carboxylate (1.5 g) in water (16.06mL) and MeOH (16.06 mL) was treated with Oxone® (5.92 g, 9.63 mmol) atroom temperature and the resulting reaction mixture was stirred for 6 h.The solution was filtered by suction and the solvent removed gavetert-butyl 4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.6 g,4.66 mmol, 97% yield) as a white solid.

A solution of tert-butyl4-((4-fluorophenyl)sulfonyl)piperidine-1-carboxylate (32.7 mg, 0.095mmol) in dioxane (238 μL) at room temperature was treated with HCl (4 Min dioxane, 190 μL, 0.762 mmol) and the resulting reaction mixture wasstirred for 4 h. The solvent was removed to give the title compound asits HCl salt (25 mg, 94%) as a white solid. ESI-MS m/z [M+H]+ 243.95.

Preparation 12 1-(2,4-difluorobenzyl)piperazine

A mixture of piperazine (26.5 g, 308 mmol) in THF (350 mL) was heated to70° C. and 1-(chloromethyl)-2,4-difluorobenzene (5 g, 30.8 mmol) wasadded. The suspension was heated at 70° C. overnight. The solid(piperazine) was filtered off, and the solvent was removed under reducedpressure. The residue was partitioned between EtOAc and water. Theorganic layer was dried and concentrated to give the title compound (6g, 92%). ESI-MS m/z [M+H]+ 213.04.

Preparation 13 4-(2-fluoro-4-methoxyphenoxy)piperidine

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.496 g,12.03 mmol) in THF (33.4 mL) at room temperature was treated with2-fluoro-4-methoxyphenol (1.181 mL, 10.03 mmol) and triphenylphosphine(3.16 g, 12.03 mmol). The reaction mixture was cooled to 0° C. and DEAD(40 wt % in toluene, 5.95 mL, 15.04 mmol) was added dropwise viasyringe. The resulting reaction mixture was stirred at 65° C. for 5 h,then at room temperature overnight. Flash silica gel chromatographyusing a gradient of 10% to 100% EtOAc in hexanes gave tert-butyl4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 85%) as alight yellow oil. ESI-MS m/z [M+Na]+ 348.2.

A solution of tert-butyl4-(2-fluoro-4-methoxyphenoxy)piperidine-1-carboxylate (2.78 g, 8.54mmol) in dioxane (21.36 mL) was treated with HCl (4 M in dioxane, 21.36mL, 85 mmol) at room temperature and the resulting reaction mixturestirred overnight. Flash silica gel chromatography using a gradient of5% to 30% MeOH in DCM gave the title compound as its HCl salt (1.7 g,76%) as a white solid. ESI-MS m/z [M+H]+ 226.20.

Preparation 14 1-(2-fluoro-4-methoxybenzyl)piperazine

A solution of 2-fluoro-4-methoxybenzaldehyde (0.910 g, 5.91 mmol) andtert-butyl piperazine-1-carboxylate (1.1 g, 5.91 mmol) in DCE (19.7 ml)was treated with sodium triacetoxyborohydride (1.752 g, 8.27 mmol) andthe resulting reaction mixture was stirred at 23° C. for 2 h. The crudematerial was purified by a flash chromatography column using a gradientof 0-50% EtOAc in heptane to give tert-butyl4-(2-fluoro-4-methoxybenzyl)piperazine-1-carboxylate (1.91 g, 100%yield) as a clear oil.

A solution of tert-butyl4-(2-fluoro-4-methoxybenzyl)piperazine-1-carboxylate (700 mg, 2.16 mmol)in DCM (10.8 mL) and TFA (10.8 mL) was stirred at 0° C. for 1 h. Afterthe solvent was removed, HPLC purification using Method A gave the titlecompound as its TFA salt (250 mg, 34.2% yield) as a white solid.ESI-MS:m/z (M+H)+ 225.1.

Preparation 15 1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine

Combined 4-(difluoromethoxy)-2-fluorobenzaldehyde (0.5 g, 2.63 mmol),tert-butyl piperazine-1-carboxylate (0.490 g, 2.63 mmol) in DCE (10 mL)and then added sodium triacetoxyhydroborate (0.780 g, 3.68 mmol) at 23°C. The reaction mixture was stirred for 18 hr at 23° C., filteredthrough Celite™, and rinsed with DCM. The resulting filtrate wasconcentrated, and the residue was purified by flash silica gelchromatography (0-10% MeOH in DCM) to give tert-butyl4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine-1-carboxylate (594.5mg, 62.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3-d) δ ppm1.41-1.49 (m, 9H), 2.41 (br. s., 4H), 3.36-3.49 (m, 4H), 3.56 (s, 2H),6.34-6.66 (m, 1H), 6.85 (dd, J=10.3, 2.4 Hz, 1H), 6.90 (dd, J=8.5, 2.2Hz, 1H), 7.33-7.48 (m, 1H); ESI-MS:m/z (M+H)+ 361.5.

Combined tert-butyl4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine-1-carboxylate (570 mg,1.58 mmol) and hydrogen chloride as a 4 M solution in dioxane (3163 μl,12.65 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 3hr. The precipitate was filtered, rinsed with dioxane (3×3 mL) and driedin vacuo to provide title compound as its hydrochloric acid salt (0.469g, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm2.78-3.56 (m, 8H), 4.29 (br, 2H), 7.15 (d, J=7.8 Hz, 1H), 7.21-7.59 (m,2H), 7.76 (br, 1H), 9.46 (br, 2H); ESI-MS:m/z (M+H)+ 261.0.

Preparation 16 4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine

Tribromoborane (34.4 ml, 34.4 mmol) was added to a suspension of4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (3.0 g, 11.46mmol) in DCM (22.9 ml) at 0° C. After 10 min, the mixture was allowed towarm to 23° C. for 3 h. The reaction mixture was quenched with waterdropwise at 0° C. until no more bubble formed upon addition, then wasallowed to warm to 23° C. Additional water (100 mL) was added to themixture and the suspension was stirred at rt for 1 h. Then the mixturewas filtered through a pad of Celite, washed with water. The layers wereseparated and the aqueous phase was washed with DCM twice. The aqueousphase was concentrated under reduced pressure to give3-fluoro-4-(piperidin-4-yloxy)phenol (3.35 g, 11.47 mmol, 100% yield) asa light-orange solid, which was used without further purification.

A solution of 3-fluoro-4-(piperidin-4-yloxy)phenol hydrobromide (16.59g, 56.8 mmol) in water (175 mL) and dioxane (100 ml) was basified withNaOH (15%) to pH=9 at 0° C., followed by addition of Boc2O (19.78 ml, 85mmol). The mixture was allowed to warm to 25° C. for 12 h. The mixturewas acidified with acetic acid to pH=7, diluted with EtOAc (100 ml) andpoured into sat. NaHCO3 (50 mL). The organic layer was separated, washedwith brine (2×30 ml), dried over Na2SO4 and concentrated in vacuo. Theresidue was purified by column chromatography using a gradient of 20-90%EtOAc in petroleum ether to give tert-butyl4-(2-fluoro-4-hydroxyphenoxy)piperidine-1-carboxylate (9.2 g, 52.0%yield) as a yellow solid. ESI-MS:m/z (M-CMe3)+ 255.7.

To a mixture of tert-butyl4-(2-fluoro-4-hydroxyphenoxy)piperidine-1-carboxylate (126 mg, 0.41mmol) and Cs2CO3 (198 mg, 0.61 mmol) in DMF (4.0 mL) was added asolution of difluoroiodomethane (1440 mg, 0.81 mmol, 10 wt %) in THF.The reaction mixture was stirred at 23° C. overnight. After the solventwas evaporated in vacuo, the residue was purified by flash silica gelchromatography (5-95% EA in heptane) to give tert-butyl4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine-1-carboxylate (18 mg,12.3% yield) as a white solid. (M+H)+ 362.0.

A solution of tert-butyl4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine-1-carboxylate (18 mg,0.05 mmol) in DCM (0.5 ml) and TFA (0.5 ml) was stirred at 0° C. for 2h. Removal of the solvent gave the title compound as its TFA salt (18mg, 0.05 mmol, 96% yield) as a white solid, which was used directly inthe next step without further purification. (M+H)+ 262.0.

Preparation 17 3-chloro-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

To a solution of 2,3-dichloro-7-methylpyrido[3,4-b]pyrazine (100 mg,0.47 mmol) in DCM (4.6 mL) was added propan-2-amine (80 μl, 0.93 mmol)and N-ethyl-N-isopropylpropan-2-amine (245 μl, 1.40 mmol) at 0° C. Theresulting solution was stirred at 0° C. for 4 h, warmed to 23° C. andstirred overnight. The solvent was removed in vacuo, and the crudematerial was dissolved in DCM (4 mL) and purified via flash columnchromatography using a gradient eluant of 0% to 100% EtOAc in heptane ona 24 g. The pure fractions were concentrated, and dried in vacuo to givethe title compound (79 mg, 0.33 mmol, 71.4% yield) as a grey solid.ESI-MS m/z [M+H]+ 237.0.

Preparation 18(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the Preparation17 using (S)-tetrahydrofuran-3-amine tosylic acid salt in place ofpropan-2-amine. ESI-MS m/z [M+H]+ 265.0.

Preparation 19(R)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the Preparation17 using (R)-tetrahydrofuran-3-amine hydrochloric acid salt in place ofpropan-2-amine, to give the title compound (41%) as a white solid.ESI-MS m/z [M+H]+ 264.9.

Preparation 203-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the Preparation17 using tetrahydrofuran-3-amine hydrochloric acid salt in place ofpropan-2-amine. ESI-MS m/z [M+H]+ 265.0.

Preparation 213-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the Preparation17 using cyclopropanamine in place of propan-2-amine. ESI-MS m/z [M+H]+235.0.

Preparation 22(1,3-cis)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol

The title compound was prepared in a manner similar to the Preparation17 using (1,3-cis)-3-aminocyclobutanol in place of propan-2-amine.ESI-MS m/z [M+H]+ 265.0.

Preparation 23(1,3-trans)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol

The title compound was prepared in a manner similar to the Preparation17 using (1,3-trans)-3-aminocyclobutanol in place of propan-2-amine.ESI-MS m/z [M+H]+ 265.0.

Preparation 243-chloro-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the Preparation17 using oxetan-3-amine in place of propan-2-amine. ESI-MS m/z [M+H]+250.9.

Preparation 253-chloro-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine

A solution of 2,3-dichloropyrido[3,4-b]pyrazine (125.0 mg, 0.584 mmol)in DCM (4.0 mL) at 0° C. was treated with1-(2-fluoro-4-methoxybenzyl)piperazine (206.0 mg, 0.642 mmol) and DIPEA(0.306 mL, 1.752 mmol). The reaction mixture was allowed to stir for 3 hat 0° C. and then at room temperature for 1 h.

After the solvent was removed in vacuo, the crude material was dissolvedin DCM (4 mL) and purified via flash silica gel chromatography using agradient eluant of 10% to 70% EtOAc in heptane. The pure fractions werecombined, concentrated via rotary evaporation, and dried in vacuo tofurnish the title compound (97 mg, 41%). ESI-MS m/z [M+H]+ 402.5.

Preparation 263-chloro-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to the Preparation25 using 4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine hydrochloridein place of 1-(2-fluoro-4-methoxybenzyl)piperazine. ESI-MS m/z [M+H]+439.3.

Preparation 273-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to the Preparation25 using 4-(2,4-difluorophenoxy)piperidine hydrochloride in place of1-(2-fluoro-4-methoxybenzyl)piperazine. ESI-MS m/z [M+H]+ 390.9.

Preparation 283-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to the Preparation25 using 1-(2,4-difluorobenzyl)piperazine hydrochloride in place of1-(2-fluoro-4-methoxybenzyl)piperazine. ESI-MS m/z [M+H]+ 389.9.

Preparation 293-chloro-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine

The title compound was prepared in a manner similar to the Preparation25 using 1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine hydrochloridein place of 1-(2-fluoro-4-methoxybenzyl)piperazine. 1H NMR (400 MHz,DMSO-d6) δ ppm 2.57-2.63 (m, 7H), 3.60 (s, 2H), 3.62-3.66 (m, 4H), 7.05(dd, J=8.3, 2.4 Hz, 1H), 7.13 (dd, J=10.7, 2.4 Hz, 1H), 7.15-7.45 (m,1H), 7.48-7.54 (m, 2H), 9.02 (s, 1H); ESI-MS m/z (M+H)+ 437.9.

EXAMPLE 13-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

A solution of 3-chloro-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine(20 mg, 0.084 mmol), 1-(2,4-difluorobenzyl)piperazine hydrochloride(33.6 mg, 0.135 mmol) and N-ethyl-N-isopropylpropan-2-amine (59.0 μl,0.338 mmol) in dioxane (0.40 mL) was heated at 60° C. overnight. Themixture was purified by HPLC Method A to gvie the title compound as itsTFA salt (43 mg, 97% yield) as a white solid. 1H NMR (400 MHz,methanol-d4) δ ppm 1.35 (d, J=6.83 Hz, 6H), 2.73 (s, 3H), 3.57 (br. s.,8H), 4.48 (s, 2H), 4.66 (quin, J=6.59 Hz, 1H), 7.11-7.24 (m, 2H), 7.61(s, 1H), 7.68 (td, J=8.54, 6.35 Hz, 1H), 8.83 (s, 1H); ESI-MS m/z [M+H]+413.0.

EXAMPLE 23-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 using 4-(2,4-difluorophenoxy)piperidinehydrochloride in place of 1-(2,4-difluorobenzyl)piperazinehydrochloride. The title compound was obtained as its TFA salt (44%yield) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.35(d, J=6.35 Hz, 6H), 1.99 (m, 2H), 2.12-2.22 (m, 2H), 2.71 (s, 3H), 3.45(ddd, J=13.06, 7.69, 3.66 Hz, 2H), 3.74-3.83 (m, 2H), 4.58 (tt, J=6.83,3.42 Hz, 1H), 4.64 (quin, J=6.71 Hz, 1H), 6.90 (dddd, J=9.34, 7.87,3.05, 1.71 Hz, 1H), 7.00 (ddd, J=11.35, 8.66, 2.93 Hz, 1H), 7.20 (td,J=9.28, 5.37 Hz, 1H), 7.56 (s, 1H), 8.73 (s, 1H); ESI-MS m/z [M+H]+414.0.

EXAMPLE 3(S)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 1-(2,4-difluorobenzyl)piperazinehydrochloride and(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine.The title compound was obtained as its TFA salt (91% yield) as a whitesolid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.09-2.18 (m, 1H), 2.42 (dtd,J=12.94, 8.18, 8.18, 6.35 Hz, 1H), 2.75 (s, 3H), 3.43-3.75 (m, 8H),3.81-3.93 (m, 2H), 4.00-4.11 (m, 2H), 4.48 (s, 2H), 4.90-4.94 (m, 1H),7.12-7.23 (m, 2H), 7.62-7.71 (m, 1H), 7.68 (s, 1H), 8.89 (s, 1H); ESI-MSm/z [M+H]+ 442.0.

EXAMPLE 4(S)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 4-(2,4-difluorophenoxy)piperidinehydrochloride and(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine.The title compound was obtained as its TFA salt (72% yield) as a whitesolid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.92-2.04 (m, 2H), 2.15-1.98(m, 3H), 2.42 (dtd, J=13.06, 8.12, 8.12, 6.35 Hz, 1H), 2.73 (s, 3H),3.44-3.55 (m, 2H), 3.76-3.93 (m, 4H), 4.01-4.11 (m, 2H), 4.58 (dt,J=6.96, 3.60 Hz, 1H), 4.88-4.92 (m, 1H), 6.85-6.93 (m, 1H), 7.00 (ddd,J=11.23, 8.54, 3.17 Hz, 1H), 7.20 (td, J=9.28, 5.37 Hz, 1H), 7.62 (s,1H), 8.79 (s, 1H); ESI-MS m/z [M+H]+ 442.0.

EXAMPLE 5(R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 4-(2,4-difluorophenoxy)piperidinehydrochloride and racemic3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine.SFC purification of the racemic product provided the free base of thetitle compound (11%) as a white solid. 1H NMR (400 MHz, methanol-d4) δppm 1.93-2.12 (m, 3H), 2.13-2.24 (m, 2H), 2.40 (ddt, J=14.40, 7.81,6.71, 6.71 Hz, 1H), 2.58 (s, 3H), 3.14-3.29 (m, 2H), 3.53-3.67 (m, 2H),3.81 (dd, J=9.03, 3.66 Hz, 1H), 3.88 (td, J=8.30, 5.86 Hz, 1H),3.99-4.04 (m, 1H), 4.06 (dd, J=9.28, 5.86 Hz, 1H), 4.48-4.58 (m, 1H),4.74 (ddt, J=7.81, 5.86, 3.91, 3.91 Hz, 1H), 6.84-6.92 (m, 1H), 6.99(ddd, J=11.23, 8.54, 3.17 Hz, 1H), 7.20 (td, J=9.28, 5.37 Hz, 1H), 7.34(s, 1H), 8.70 (s, 1H); ESI-MS m/z [M+H]+ 442.0.

EXAMPLE 6(R)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 1-(2,4-difluorobenzyl)piperazinehydrochloride and racemic3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine.SFC purification of the racemic product provided the TFA salt of thetitle compound (39%) as a white solid. 1H NMR (400 MHz, methanol-d4) δppm 1.92-2.11 (m, 1H) 2.34-2.44 (m, 1H) 2.58 (s, 3H) 2.74 (t, J=4.39 Hz,4H) 3.33-3.40 (m, 4H) 3.68 (s, 2H) 3.79 (dd, J=9.28, 3.91 Hz, 1H) 3.87(td, J=8.42, 6.10 Hz, 1H) 3.98-4.02 (m, 1H) 4.04 (dd, J=9.28, 5.86 Hz,1H) 4.73 (ddt, J=7.57, 5.86, 4.03, 4.03 Hz, 1H) 6.89-7.01 (m, 2H) 7.33(s, 1H) 7.45-7.53 (m, 1H) 8.68 (s, 1H); ESI-MS m/z [M+H]+ 442.0.

EXAMPLE 7N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 1-(2,4-difluorobenzyl)piperazinehydrochloride and3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine. The titlecompound was obtained as its TFA salt (22% yield) as a white solid film.1H NMR (500 MHz, methanol-d4) δ ppm 0.77-0.86 (m, 2H) 0.94-1.04 (m, 2H)2.75 (s, 3H) 3.13 (tt, J=7.44, 3.78 Hz, 1H) 3.54 (br. s., 8H) 4.48 (s,2H) 7.12-7.25 (m, 2H) 7.66 (td, J=8.54, 6.35 Hz, 1H) 7.71 (s, 1H) 8.88(s, 1H); ESI-MS m/z [M+H]+ 411.0.

EXAMPLE 8N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine2,2,2-trifluoroacetate

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride and3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine. The titlecompound was obtained as its TFA salt (85% yield) as a white solid. 1HNMR (400 MHz, methanol-d4) δ ppm 0.78-0.83 (m, 2H) 0.94-0.99 (m, 2H)1.89-1.99 (m, 2H) 2.07-2.14 (m, 2H) 2.72 (s, 3H) 3.11 (tt, J=7.44, 3.78Hz, 1H) 3.37-3.43 (m, 2H) 3.71-3.78 (m, 5H) 4.43 (tt, J=6.83, 3.42 Hz,1H) 6.67 (ddd, J=9.28, 2.93, 1.46 Hz, 1H) 6.74 (dd, J=12.69, 2.93 Hz,1H) 7.07 (t, J=9.28 Hz, 1H) 7.63 (s, 1H) 8.76 (s, 1H); ESI-MS m/z [M+H]+424.0.

EXAMPLE 9(1,3-cis)-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-ylamino)cyclobutanol

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 4-(2,4-difluorophenoxy)piperidinehydrochloride and(1,3-cis)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol.The title compound was obtained as its TFA salt (4.1% yield) as a whitesolid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.95-2.10 (m, 4H), 2.16-2.24(m, 2H), 2.58 (s, 3H), 2.83-2.92 (m, 2H), 3.22-3.29 (m, 2H), 3.58-3.66(m, 2H), 4.07-4.14 (m, 1H), 4.19 (tt, J=8.91, 6.96 Hz, 1H), 4.55 (tt,J=7.32, 3.66 Hz, 1H), 6.84-6.94 (m, 1H), 7.01 (ddd, J=11.23, 8.30, 2.93Hz, 1H), 7.21 (td, J=9.28, 5.37 Hz, 1H), 7.32 (s, 1H), 8.68 (s, 1H);ESI-MS m/z [M+H]+ 441.9.

EXAMPLE 10(1,3-cis)-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol

The title compound was prepared and purified in a manner similar to thepreparation of Example 1 by coupling 1-(2,4-difluorobenzyl)piperazinehydrochloride and(1,3-cis)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol.The title compound was obtained as its TFA salt (5.0% yield) as a whitesolid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.96-2.01 (m, 2H), 2.58 (s,3H), 2.77 (t, J=4.88 Hz, 4H), 2.86 (dtd, J=9.28, 6.83, 6.83, 2.93 Hz,2H), 3.36 (s, 1H), 3.38 (br. s., 4H), 3.70 (s, 2H), 4.06-4.13 (m, 1H),4.17 (tt, J=8.97, 7.14 Hz, 1H), 6.89-7.06 (m, 2H), 7.32 (s, 1H), 7.50(td, J=8.54, 6.35 Hz, 1H), 8.66 (s, 1H); ESI-MS m/z [M+H]+ 441.0.

EXAMPLE 113-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-((1,3-trans)-3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine

To a solution of(1,3-cis)-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol(50 mg, 0.113 mmol) in DCM (2.3 mL) was added DAST (19.45 μl, 0.147mmol) at 0° C. After the reaction was stirred for 2 h at thistemperature, the reaction was warmed up to 23° C. and stirred overnight.The reaction was quenched with ice, followed by sat. NaHCO3, andvigorously stirred for 10 min. Then the mixture was extracted with EA(10 mL×2). After the solvent was removed in vacuo, the residue waspurified by HPLC Method A to gvie the title compound as its TFA salt(3.8 mg, 7.6% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δppm 1.97-2.04 (m, 2H), 2.13-2.21 (m, 2H), 2.56-2.66 (m, 2H), 2.67-2.79(m, 2H), 2.72 (s, 3H), 3.46-3.54 (m, 2H), 3.76-3.86 (m, 2H), 4.59 (tt,J=7.02, 3.48 Hz, 1H), 4.92-5.01 (m, 1H), 5.28 (dtt, J=40, 6.22, 2.81 Hz,1H), 6.87-6.93 (m, 1H), 7.01 (ddd, J=11.35, 8.42, 3.17 Hz, 1H), 7.20(td, J=9.15, 5.61 Hz, 1H), 7.62 (s, 1H), 8.78 (s, 1H); ESI-MS m/z [M+H]+443.9.

EXAMPLE 123-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-((1,3-trans)-3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to the preparationof Example using(1,3-cis)-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanolas the substrate. The title compound was purified by HPLC (Method A),followed by a flash chromatography column (5-10% MeOH in DCM), tofurnish its free base (4.1% yield) as a white solid. 1H NMR (400 MHz,methanol-d4) δ ppm 2.48-2.57 (m, 2H), 2.58 (s, 3H), 2.64-2.72 (m, 2H),2.72-2.78 (m, 4H), 3.37 (d, J=4.88 Hz, 4H), 3.70 (d, J=0.98 Hz, 2H),4.77-4.83 (m, 1H), 5.14-5.36 (m, 1H), 6.92-7.14 (m, 2H), 7.34 (s, 1H),7.50 (td, J=8.54, 6.83 Hz, 1H), 8.68 (s, 1H); ESI-MS m/z [M+H]+ 443.0.

EXAMPLE 13(1,3-trans)-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol

The title compound was prepared in a manner similar to the preparationof Example 1 by coupling 4-(2,4-difluorophenoxy)piperidine hydrochlorideand(1,3-trans)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol.The title compound was purified by a flash column chromatography (0-20%MeOH in DCM), to furnish its free base (80% yield) as a light yellowsolid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.00-2.07 (m, 2H), 2.16-2.24(m, 2H), 2.43-2.48 (m, 4H), 2.58 (s, 3H), 3.19-3.30 (m, 2H), 3.57-3.67(m, 2H), 4.47-4.52 (m, 1H), 4.54 (td, J=7.32, 3.42 Hz, 1H), 4.71 (quin,J=6.71 Hz, 1H), 6.86-6.93 (m, 1H), 7.00 (ddd, J=11.35, 8.42, 3.17 Hz,1H), 7.21 (td, J=9.28, 5.37 Hz, 1H), 7.33 (s, 1H), 8.68 (s, 1H); ESI-MSm/z [M+H]+ 441.9.

EXAMPLE 14(1,3-trans)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol

The title compound was prepared in a manner similar to the preparationof Example 1 by coupling 1-(2,4-difluorobenzyl)piperazine hydrochlorideand(1,3-trans)-3-((3-chloro-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol.The title compound was purified by a flash column chromatography (0-20%MeOH in DCM), to furnish its free base (88% yield) as a light yellowsolid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.62 (dd, J=6.83, 5.86 Hz,4H), 1.76 (s, 3H), 1.95 (t, J=4.64 Hz, 4H), 2.54-2.59 (m, 4H), 2.88 (s,2H), 3.67 (quin, J=5.74 Hz, 1H), 3.88 (quin, J=6.83 Hz, 1H), 6.00-6.26(m, 2H), 6.51 (s, 1H), 6.62-6.73 (m, 1H), 7.86 (s, 1H); ESI-MS m/z[M+H]+ 441.0.

EXAMPLE 153-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine

Combined 3-chloro-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine(26.0 mg, 0.104 mmol), 1-(2,4-difluorobenzyl)piperazine (55.0 mg, 0.259mmol), and acetonitrile (1 mL) then addedN-ethyl-N-isopropylpropan-2-amine (0.054 mL, 0.311 mmol) at 23° C. Thereaction mixture was stirred at 50° C. for 7 h, cooled to 23° C., andconcentrated in vacuo. The resulting residue was diluted with saturatedNH4Cl (1 mL) and the crude product was extracted with EtOAc (2 mL). Theorganic layer was separated, washed with brine (1 mL), dried overNa2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crudematerial was purified by flash column chromatography using a gradient of10-100% EtOAc in heptane to provide the free base of the title compound(37.3 mg, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm2.51 (s, 3H), 2.68 (br. s., 4H), 3.30 (br. s., 4H), 3.64 (br. s., 2H),4.65 (t, J=6.6 Hz, 2H), 4.81 (t, J=7.1 Hz, 2H), 4.96-5.05 (m, 1H), 7.10(td, J=8.5, 2.4 Hz, 1H), 7.20-7.28 (m, 2H), 7.46-7.56 (m, 1H), 7.75 (d,J=4.9 Hz, 1H), 8.70 (s, 1H); ESI-MS: m/z (M+H)+ 427.0.

EXAMPLE 163-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 15 by using 4-(2,4-difluorophenoxy)piperidinehydrochloride to furnish its free base (66.8% yield) as an off-whitesolid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93-2.00 (m, 2H), 2.14 (ddd,J=9.5, 6.3, 3.2 Hz, 2H), 2.51 (br. s., 3H), 3.16 (ddd, J=12.6, 9.4, 2.9Hz, 2H), 3.53-3.64 (m, 2H), 4.57-4.64 (m, 1H), 4.67 (t, J=6.6 Hz, 2H),4.83 (t, J=6.8 Hz, 2H), 4.99-5.08 (m, 1H), 7.00-7.06 (m, 1H), 7.22 (s,1H), 7.27-7.37 (m, 2H), 7.81 (d, J=4.9 Hz, 1H), 8.70 (s, 1H); ESI-MS:m/z(M+H)+ 428.0.

EXAMPLE 173-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar to thepreparation of Example 15 by using4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine hydrochloride tofurnish its free base (71.7% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 1.91-2.03 (m, 2H), 2.15 (ddd, J=9.5, 6.1, 3.4 Hz,2H), 2.51 (br. s., 3H), 3.11-3.22 (m, 2H), 3.53-3.64 (m, 2H), 4.61-4.70(m, 3H), 4.83 (t, J=6.8 Hz, 2H), 4.98-5.08 (m, 1H), 6.98-7.02 (m, 1H),7.02-7.33 (m, 3H), 7.36 (t, J=9.5 Hz, 1H), 7.81 (d, J=4.9 Hz, 1H), 8.70(s, 1H); ESI-MS: m/z (M+H)+ 476.0.

EXAMPLE 183-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

Combined 4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidine hydrochloride(41 mg, 0.137 mmol),3-chloro-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine (13 mg, 0.055mmol), and N-ethyl-N-isopropylpropan-2-amine (21 mg, 0.165) inacetonitrile (0.55 mL). The reaction vessel was sealed and heated to 90°C. for 6 h and then allowed to cool to room temperature. The crudesolution was purified via HPLC using method A to give the title compoundas a yellow semi-solid (11 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ ppm1.34 (d, J=5.86 Hz, 6H), 2.05-2.13 (m, 4H), 2.81 (s, 3H), 3.63-3.65 (m,2H), 3.83-3.87 (m, 2H), 4.34-4.35 (m, 1H), 4.57 (m, 1H), 5.08-5.10 (m,1H), 6.47 (t, J=60 Hz, 1H), 6.96-6.97 (m, 1H), 6.97-6.99 (m, 2H), 7.53(s, 1H), 8.98 (s, 1H); ESI-MS m/z [M+H]+ 462.4.

EXAMPLE 19N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 18 using3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine and3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine to give thetitle compound (60.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6)δ ppm 0.80-0.86 (m, 4H), 1.86-1.88 (m, 2H), 2.07-2.09 (m, 2H), 2.64 (s,3H), 3.11-3.12 (m, 1H), 3.29-3.31 (m, 2H), 3.64-3.67 (m, 2H), 4.67-4.68(m, 1H), 6.99-7.36 (m, 4H), 7.65 (s, 1H), 8.45 (d, J=4.39 Hz, 1H), 8.97(s, 1H); ESI-MS m/z [M+H]+ 460.4.

EXAMPLE 20(R)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 18 using(R)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineto give the title compound (63.2% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 2.08-2.09 (m, 2H), 2.10-2.11 (m, 3H), 2.35 (m, 1H),2.64 (s, 3H), 3.33-3.37 (m, 2H), 3.71-3.75 (m, 4H), 3.92-3.98 (m, 2H),4.69-4.75 (m, 2H), 6.99-7.37 (m, 4H), 7.62 (s, 1H), 8.39 (d, J=6.35 Hz,1H), 8.98 (s, 1H); ESI-MS m/z [M+H]+ 490.4.

EXAMPLE 21(S)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 18 using(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineto give the title compound (67.7% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 2.08-2.09 (m, 2H), 2.10-2.11 (m, 3H), 2.35 (m, 1H),2.64 (s, 3H), 3.33-3.37 (m 2H), 3.71-3.75 (m, 4H), 3.78-3.98 (m, 2H),4.69-4.75 (m, 2H), 6.99-7.37 (m, 4H), 7.62 (s, 1H), 8.39 (d, J=6.35 Hz,1H), 8.98 (s, 1H); ESI-MS m/z [M+H]+ 490.4.

EXAMPLE 223-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

Combined 1-(2-fluoro-4-methoxybenzyl)piperazine TFA (44 mg, 0.137 mmol),3-chloro-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine (13 mg, 0.055mmol), and N-ethyl-N-isopropylpropan-2-amine (21 mg, 0.165 mmol) inacetonitrile (0.55 mL). The reaction vessel was sealed and heated to 90°C. for 8 h and then allowed to cool to room temperature. The crudesolution was purified by HPLC using method B to give the title compoundas a white solid (4 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24(d, J=6.83 Hz, 6H), 2.64 (s, 3H), 3.23-3.28 (m, 4H), 3.30-3.36 (m, 4H),3.58 (s, 2H), 3.77 (s, 3H), 4.35-4.39 (m, 1H), 6.79-6.83 (m, 3H), 7.24(s, 1H), 7.34 (m, 1H), 8.66 (s, 1H); ESI-MS m/z [M+H]+ 425.6.

EXAMPLE 23N-cyclopropyl-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar toExample 22 using3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine to give thetitle compound as a white solid (27.8% yield). 1H NMR (400 MHz, DMSO-d6)δ ppm 0.66-0.67 (m, 2H), 0.76-0.79 (m, 2H), 2.62 (s, 3H), 2.89 (dd,J=7.32, 3.91 Hz, 1H), 3.18-3.20 (m, 4H), 3.30-3.34 (m, 4H), 3.56 (s,2H), 3.77 (s, 3H), 6.77-6.83 (m, 2H), 7.20 (d, J=2.93 Hz, 1H), 7.29-7.34(m, 2H), 8.68 (s, 1H); ESI-MS m/z [M+H]+ 423.5.

EXAMPLE 24(R)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar toExample 22 using(R)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineto give the title compound (39% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 2.03-2.05 (m, 1H), 2.23-2.25 (m, 1H), 2.64 (s, 3H),3.23-3.25 (m, 4H), 3.30-3.34 (m, 4H), 3.57 (s, 2H), 3.66-3.67 (m, 1H),3.75-3.76 (m, 1H), 3.77 (s, 3H), 3.88-3.89 (m, 1H), 3.95-3.96 (m, 1H),4.59-4.62 (m, 1H), 6.77-6.82 (m, 2H), 7.01 (d, J=6.35 Hz, 1H), 7.25 (s,1H), 7.33-7.35 (m, 1H), 8.68 (s, 1H); ESI-MS m/z [M+H]+ 453.4.

EXAMPLE 25(S)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared and purified in a manner similar toExample 22 using(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineto give the title compound (39% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ ppm 2.03-2.05 (m, 1H), 2.23-2.25 (m, 1H), 2.64 (s, 3H),3.23-3.25 (m, 4H), 3.30-3.34 (m, 4H), 3.57 (s, 2H), 3.64-3.66 (m, 1H),3.67-3.69 (m, 1H), 3.77 (s, 3H), 3.92-3.94 (m, 1H), 3.95-3.96 (m, 1H),4.59-4.63 (m, 1H), 6.77-6.82 (m, 2H), 7.01 (d, J=5.86 Hz, 1H), 7.25 (s,1H), 7.33-7.35 (m, 1H), 8.68 (s, 1H); ESI-MS m/z [M+H]+ 453.4.

EXAMPLE 263-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 22 using3-chloro-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine and1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine hydrochloride. Thetitle compound was purified by HPLC using Method B to give its free base(75% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm1.24 (d, J=6.8 Hz, 6H), 2.50 (s, 3H), 2.60-2.74 (m, 4H), 3.23 (br. s.,4H), 3.63 (s, 2H), 4.31-4.43 (m, 1H), 6.73 (d, J=8.3 Hz, 1H), 7.05 (dd,J=8.5, 2.2 Hz, 1H), 7.13 (dd, J=10.7, 2.4 Hz, 1H), 7.15-7.46 (m, 2H),7.51 (t, J=8.5 Hz, 1H), 8.66 (s, 1H); ESI-MS: m/z (M+H)+ 461.0.

EXAMPLE 27N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 22 using3-chloro-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine and1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine hydrochloride. Thetitle compound was purified by HPLC using Method B to give its free base(85% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm0.62-0.72 (m, 2H), 0.72-0.82 (m, 2H), 2.52 (s, 3H), 2.57-2.76 (m, 4H),2.90 (tq, J=7.3, 3.8 Hz, 1H), 3.21 (br. s., 4H), 3.63 (br. s., 2H), 7.05(dd, J=8.5, 2.2 Hz, 1H), 7.13 (dd, J=11.0, 2.2 Hz, 1H), 7.15-7.46 (m,3H), 7.50 (t, J=8.3 Hz, 1H), 8.70 (s, 1H); ESI-MS: m/z (M+H)+ 459.0.

EXAMPLE 28(R)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 22 using(R)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineand 1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine hydrochloride. Thetitle compound was purified by HPLC using Method B to give its free base(61.4% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm2.00-2.08 (m, 1H), 2.19-2.28 (m, 1H), 2.51 (s, 3H), 2.58-2.81 (m, 4H),3.27 (br. s., 4H), 3.58-3.70 (m, 3H), 3.74 (td, J=8.2, 6.1 Hz, 1H),3.85-3.92 (m, 1H), 3.95 (dd, J=8.8, 6.3 Hz, 1H), 4.58-4.66 (m, 1H), 7.05(dd, J=8.5, 2.2 Hz, 1H), 7.09 (d, J=5.4 Hz, 1H), 7.14 (dd, J=11.0, 2.2Hz, 1H), 7.15-7.46 (m, 2H), 7.51 (t, J=8.5 Hz, 1H), 8.70 (s, 1H);ESI-MS: m/z (M+H)+ 489.0.

EXAMPLE 29(S)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine

The title compound was prepared in a manner similar to Example 22 using(S)-3-chloro-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amineand 1-(4-(difluoromethoxy)-2-fluorobenzyl)piperazine hydrochloride. Thetitle compound was purified by HPLC using Method B to give its free base(63.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm2.00-2.08 (m, 1H), 2.23 (dtd, J=12.7, 7.8, 7.8, 6.3 Hz, 1H), 2.52 (s,3H), 2.55-2.96 (m, 4H), 3.27 (br. s., 4H), 3.53-3.70 (m, 3H), 3.74 (td,J=8.1, 5.9 Hz, 1H), 3.85-3.92 (m, 1H), 3.95 (dd, J=8.8, 6.3 Hz, 1H),4.57-4.67 (m, 1H), 7.05 (dd, J=8.3, 2.0 Hz, 1H), 7.08-7.47 (m, 4H), 7.52(t, J=8.5 Hz, 1H), 8.70 (s, 1H); ESI-MS: m/z (M+H)+ 489.0.

EXAMPLE 302-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine2,2,2-trifluoroacetate

A solution of3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine(15 mg, 0.038 mmol), propan-2-amine (29.7 μl, 0.345 mmol) and DIPEA(20.12 μl, 0.115 mmol) in MeCN (0.19 mL) was heated at 90° C. overnight.The title compound was purified by HPLC using Method A to furnish itsTFA salt (16.0 mg, 79% yield) as a white solid. 1H NMR (400 MHz,methanol-d4) δ ppm 1.33 (d, J=6.83 Hz, 7H), 2.75 (s, 3H), 3.54 (br. s.,4H), 4.03 (br. s., 4H), 4.36-4.57 (m, 3H), 7.05-7.25 (m, 2H), 7.66 (td,J=8.54, 6.35 Hz, 1H), 7.78 (s, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]+413.0.

Example 312-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine2,2,2-trifluoroacetate

The title compound was prepared and purified in a manner similar to thepreparation of Example 30 by coupling3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazineand 10 equivalents of cyclopropanamine at 110° C. The title compound wasobtained as its TFA salt (15.9% yield) as a yellow solid. 1H NMR (400MHz, methanol-d4) δ ppm 0.64-0.78 (m, 2H) 0.85-0.96 (m, 2H) 2.76 (s, 4H)2.89-2.98 (m, 1H) 3.51 (br. s., 5H) 3.84-4.16 (m, 4H) 4.46 (s, 3H)7.01-7.24 (m, 2H) 7.65 (td, J=8.42, 6.10 Hz, 1H) 7.81 (s, 1H) 8.91 (s,1H); ESI-MS m/z [M+H]+ 411.0.

EXAMPLE 32(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using(S)-tetrahydrofuran-3-amine hydrochloride and3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazineto give the title compound (14.8% yield) as a white solid. 1H NMR (400MHz, MeOD-d4) δ ppm 2.03-2.05 (m, 1H), 2.38-2.40 (m, 1H), 2.58 (s, 3H),2.65-2.77 (m, 4H), 3.41-3.58 (m, 4H), 3.66 (s, 2H), 3.79 (dd, J=9.28,3.91 Hz, 1H), 3.86 (m, 1H), 3.87 (m, 1H), 4.06 (dd, J=9.28, 5.86 Hz,1H), 4.69 (m, 1H), 6.91-7.01 (m, 2H), 7.39 (s, 1H), 7.49 (m, 1H), 8.69(s, 1H); ESI-MS m/z [M+H]+ 441.4.

EXAMPLE 33(R)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using(R)-tetrahydrofuran-3-amine hydrochloride and3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazineto give the title compound (8.9% yield) as a white solid. 1H NMR (400MHz, MeOD-d4) δ ppm 2.02-2.03 (m, 1H), 2.36-2.37 (m, 1H), 2.58 (s, 3H),2.68-2.73 (m, 4H), 3.45-3.66 (m, 4H), 3.79 (s, 2H), 3.80 (dd, J=9.28,3.91 Hz, 1H), 3.86 (m, 1H), 3.87 (m, 1H), 4.06 (dd, J=9.28, 5.86 Hz,1H), 4.69 (m, 1H), 6.94-6.98 (m, 2H), 7.40 (s, 1H), 7.47 (m, 1H), 8.68(s, 1H); ESI-MS m/z [M+H]+ 441.4.

EXAMPLE 34N-cyclopropyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using10 equivalents of cyclopropanamine and3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazineat 110° C. to give the title compound (23.8% yield) as a dark yellowsemi-solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 0.70-0.74 (m, 2H), 0.88-0.90(m, 2H), 2.71 (s, 3H), 2.90 (dt, J=7.44, 3.36 Hz, 1H), 3.77-3.80 (m,2H), 3.99-4.02 (m, 2H), 4.57-4.58 (m, 1H), 6.87-6.89 (m, 1H), 6.99-7.01(m, 1H), 7.18-7.19 (m, 1H), 7.65 (s, 1H), 8.73 (s, 1H); ESI-MS m/z[M+H]+ 412.4.

EXAMPLE 352-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using10 equivalents of propan-2-amine and3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazineat 110° C. to give the title compound (15.6% yield) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ ppm 1.32 (d, J=6.35 Hz, 6H), 1.93-1.96 (m,2H), 2.09-2.11 (m, 2H), 2.70 (s, 3H), 3.83-3.84 (m, 2H), 4.05-4.06 (m2H), 4.42-4.44 (m, 1H), 6.89 (m, 1H), 7.00-7.02 (m, 1H), 7.19-7.20 (m,1H), 7.62 (s, 1H), 8.64 (s, 1H); ESI-MS m/z [M+H]+ 414.4.

EXAMPLE 36(R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using(R)-tetrahydrofuran-3-amine hydrochloride and3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazineto give the title compound (11.8% yield) as a yellow solid. 1H NMR (400MHz, MeOD-d4) δ ppm 2.08-2.09 (m, 2H), 2.10-2.12 (m, 3H), 2.35-2.36 (m,1H), 2.71 (s, 3H), 3.82-3.86 (m 4H), 4.04-4.07 (m, 4H), 4.60 (m, 1H),4.67 (m, 1H), 6.89 (m, 1H), 7.00-7.02 (m, 1H),7.17-7.19 (m, 1H), 7.64 (s1H), 8.69 (s, 1H); ESI-MS m/z [M+H]+ 442.4.

EXAMPLE 37(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 30 using(S)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate and3-chloro-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazineto give the title compound (2.1% yield) as a yellow solid. 1H NMR (400MHz, MeOD-d4) δ ppm 2.08-2.09 (m, 2H), 2.10-2.11 (m, 3H), 2.35-2.36 (m,1H), 2.70 (s, 3H), 3.82-3.86 (m 4H), 4.04-4.07 (m, 4H), 4.60 (m, 1H),4.67 (m, 1H), 6.89 (m, 1H), 7.00-7.01 (m, 1H),7.17-7.19 (m, 1H), 7.64 (s1H), 8.69 (s, 1H); ESI-MS m/z [M+H]+ 442.4.

EXAMPLE 382-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine

Combined3-chloro-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazine(30 mg, 0.068 mmol), propan-2-amine (40 mg, 0.680 mmol), andN-ethyl-N-isopropylpropan-2-amine (132 mg, 1.02 mmol) in acetonitrile(1.00 mL). The reaction vessel was sealed and heated to 120° C. for 16 hand then allowed to cool to room temperature. The crude solution waspurified by HPLC using Method A to give the title compound as a yellowsolid (6 mg, 16%). 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=5.86, Hz,6H), 2.01-2.13 (m, 4H), 2.81 (m, 3H), 3.63-3.65 (m, 2H), 3.83-3.87 (m,2H), 4.34-4.35 (m, 1H), 4.57 (m, 1H), 5.08-5.10 (m, 1H), 6.47 (t, J=60Hz, 1H), 6.96-6.97 (m, 1H), 6.98-7.01 (m, 2H), 7.53 (s, 1H), 8.98 (s,1H); ESI-MS m/z [M+H]+ 462.4.

EXAMPLE 39N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 38 using cyclopropanamine to give the title compound (18.4%yield) as a yellow film. 1H NMR (400 MHz, CDCl3) δ ppm 0.64-0.66 (m,2H), 0.96-0.99 (m, 2H), 2.01-2.12 (m, 4H), 2.80 (m, 3H), 2.94-2.96 (m,1H), 3.63-3.65 (m, 2H), 3.79-3.84 (m, 2H), 4.55 (dt, J=6.22, 2.99 Hz,1H), 6.46 (t, J=70.3 Hz, 1H), 6.95-7.03 (m, 3H), 7.51 (s, 1H), 9.01 (s,1H); ESI-MS m/z [M+H]+ 460.4.

EXAMPLE 40(R)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 38 using (R)-tetrahydrofuran-3-amine hydrochloride to give thetitle compound (17.4% yield) as a yellow film. 1H NMR (400 MHz, CDC13) δppm 1.95-2.12 (m, 5H), 2.35-2.45 (m, 1H), 2.80 (s, 3H), 3.60-3.76 (m,2H), 3.87-3.95 (m, 6H), 4.56-4.57 (m, 1H), 4.73-4.74 (m, 1H), 5.53 (brs, 1H), 6.46 (t, J=73.2 Hz, 1H), 6.95-7.04 (m, 3H), 7.52 (s, 1H), 8.99(s, 1H); ESI-MS m/z [M+H]+ 490.4.

EXAMPLE 41(S)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 38 using (S)-tetrahydrofuran-3-amine hydrochloride to give thetitle compound (17.5% yield) as a yellow film. 1H NMR (400 MHz, CDCl3) δppm 1.95-2.12 (m, 5H), 2.35-2.45 (m, 1H), 2.80 (s, 3H), 3.62-3.77 (m,2H), 3.88-3.95 (m, 6H), 4.56-4.57 (m, 1H), 4.73-4.74 (m, 1H), 5.51 (brs, 1H), 6.46 (t, J=73.3 Hz, 1H), 6.96-7.02 (m, 3H), 7.53 (s, 1H), 8.98(s, 1H); ESI-MS m/z [M+H]+ 490.4.

EXAMPLE 422-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 38 usingpropan-2-amine and3-chloro-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine.The title compound was purified by HPLC using Method B to give its freebase (25.6% yield) as a yellow semi-solid. 1H NMR (400 MHz, CDCl3) δ ppm1.31 (d, J=6.35 Hz, 6H), 2.63 (s, 3H), 2.66-2.68 (m, 4H), 3.34-3.36 (m,4H), 3.62 (s, 2H), 3.81 (s, 3H), 4.32-4.36 (m, 1H), 4.98-5.00 (m, 1H),6.63 (dd, J=11.72, 2.44 Hz, 1H), 6.70 (dd, J=8.79, 2.44 Hz, 1H),7.26-7.32 (m, 1H) 7.36 (s, 1H),8.89 (s, 1H); ESI-MS m/z [M+H]+ 425.4.

EXAMPLE 43N-cyclopropyl-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 38 usingcyclopropanamine and3-chloro-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine.The title compound was purified by HPLC using Method B to give its freebase (19.8% yield) as a white solid. 1H NMR (400 MHz, CDC13) δ ppm0.59-0.61 (m, 2H), 0.92-0.94 (m, 2H), 2.66 (s, 3H), 2.67-2.69 (m, 4H),2.91-2.93 (m, 1H), 3.36-3.40 (m, 4H), 3.66 (s, 2H), 3.81 (s, 3H), 6.63(dd, J=11.72, 2.44 Hz, 1H), 6.71 (dd, J=8.79, 2.44 Hz, 1H), 7.27-7.28(m, 1H), 7.39 (s, 1H), 8.99 (s, 1H); ESI-MS m/z [M+H]+ 423.4.

EXAMPLE 44(R)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 38 using(R)-tetrahydrofuran-3-amine hydrochloride and3-chloro-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine.The title compound was purified by HPLC using Method B to give its freebase (7.0% yield) as a yellow film. 1H NMR (400 MHz, CDCl3) δ ppm1.91-1.92 (m, 1H), 2.43-2.45 (m, 1H), 2.65 (s, 3H), 2.67-2.70 (m, 4H),3.39-3.43 (m, 4H), 3.79 (s, 2H), 3.81 (s, 3H), 3.85-3.87 (m, 2H),4.01-4.02 (m, 2H), 4.72-4.74 (m, 1H), 5.23-5.24 (m, 1H), 6.63 (dd,J=11.72, 2.44 Hz, 1H), 6.69-6.72 (M, 1H), 7.27-7.28 (m, 1H), 7.39 (s,1H), 8.91 (s, 1H); ESI-MS m/z [M+H]+ 453.4.

EXAMPLE 45(S)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared in a manner similar to Example 38 using(S)-tetrahydrofuran-3-amine hydrochloride and3-chloro-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine.The title compound was purified by HPLC using Method B to give its freebase (4.4% yield) as a yellow film. 1H NMR (400 MHz, CDCl3) δ ppm1.90-1.92 (m, 1H), 2.42-2.43 (m, 1H), 2.66 (s, 3H), 2.67-2.70 (m, 4H),3.41-3.45 (m, 4H), 3.79 (s, 2H), 3.81 (s, 3H), 3.85-3.87 (m, 2H),4.01-4.02 (m, 2H), 4.72-4.74 (m, 1H), 5.23-5.24 (m, 1H), 6.63 (dd,J=11.72, 2.44 Hz, 1H), 6.69-6.72 (m, 1H), 7.27-7.28 (m, 1H), 7.39 (s,1H), 8.92 (s, 1H); ESI-MS m/z [M+H]+ 453.4.

EXAMPLE 462-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine

Combined3-chloro-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine(20.0 mg, 0.046 mmol), potassium fluoride (3.45 mg, 0.059 mmol), andDMSO (0.1 mL) then added N-ethyl-N-isopropylpropan-2-amine (0.032 mL,0.183 mmol) and propan-2-amine (0.012 mL, 0.137 mmol) at 23° C. Thereaction mixture was stirred at 23° C. for 1 h and then at 50° C. for 16h. The reaction mixture was diluted with water (0.4 mL) to furnish agummy solid. The mother liquor was decanted and the crude residue waspurified by HPLC using Method B to give free base of title compound (2.9mg, 13.79% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm1.23 (d, J=6.8 Hz, 6H), 2.51 (br. s., 3H), 2.57-2.70 (m, 4H), 3.35 (br.s., 4H), 3.60 (br. s., 2H), 4.26-4.36 (m, 1H), 6.33 (d, J=7.8 Hz, 1H),7.04 (dd, J=8.5, 2.2 Hz, 1H), 7.13 (dd, J=10.7, 2.4 Hz, 1H), 7.15-7.45(m, 2H), 7.50 (t, J=8.3 Hz, 1H), 8.66 (s, 1H); ESI-MS: m/z (M+H)+ 461.0.

EXAMPLE 47N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 46 using cyclopropanamine to give its free base (22.9% yield) asa yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.61-0.69 (m, 2H),0.71-0.81 (m, 2H), 2.52 (s, 3H), 2.53-2.80 (m, 5H), 2.84 (tq, J=7.1, 3.6Hz, 1H), 3.36 (br. s., 4H), 3.61 (br. s., 2H), 6.97 (br. s., 1H), 7.05(dd, J=8.8, 2.0 Hz, 1H), 7.10-7.15 (m, 1H), 7.15-7.45 (m, 2H), 7.50 (t,J=8.5 Hz, 1H), 8.74 (s, 1H); ESI-MS:m/z (M+H)+ 459.0.

EXAMPLE 48(R)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 46 using (R)-tetrahydrofuran-3-amine hydrochloride to give itsfree base (48.8% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δppm 1.98-2.05 (m, 1H), 2.19-2.28 (m, 1H), 2.51 (s, 3H), 2.57-2.67 (m,4H), 3.33-3.45 (m, 4H), 3.59 (s, 2H), 3.65 (dd, J=8.8, 4.4 Hz, 1H), 3.74(td, J=8.1, 6.3 Hz, 1H), 2.50 (d, J=2.0 Hz, 1H), 3.97 (dd, J=8.8, 6.3Hz, 1H), 4.51-4.59 (m, 1H), 6.67 (d, J=5.9 Hz, 1H), 7.04 (dd, J=8.5, 2.2Hz, 1H), 7.12 (dd, J=10.7, 2.4 Hz, 1H), 7.14-7.45 (m, 2H), 7.50 (t,J=8.3 Hz, 1H), 8.68 (s, 1H); ESI-MS: m/z (M+H)+ 489.0.

EXAMPLE 49(S)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine

The title compound was prepared and purified in a manner similar toExample 46 using (S)-tetrahydrofuran-3-amine hydrochloride to give itsfree base (46.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δppm 1.96-2.06 (m, 1H), 2.18-2.30 (m, 1H), 2.51 (s, 3H), 2.56-2.71 (m,4H), 3.33-3.48 (m, 4H), 3.59 (s, 2H), 3.63-3.68 (m, 1H), 3.74 (td,J=8.2, 6.1 Hz, 1H), 3.83-3.91 (m, 1H), 3.97 (dd, J=8.8, 6.3 Hz, 1H),4.50-4.60 (m, 1H), 6.69 (d, J=5.9 Hz, 1H), 7.04 (dd, J=8.3, 2.4 Hz, 1H),7.13 (dd, J=10.7, 2.4 Hz, 1H), 7.14-7.46 (m, 2H), 7.50 (t, J=8.5 Hz,1H), 8.68 (s, 1H); ESI-MS: m/z (M+H)+ 489.0.

EXAMPLE 502-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-3-amine

Combined3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazine(20 mg, 0.051 mmol), potassium fluoride (3.87 mg, 0.067 mmol), and DMSO(0.1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.018 mL, 0.103mmol) and oxetan-3-amine (10.71 μl, 0.154 mmol) at 23° C. The reactionmixture was stirred at 23° C. for 48 h. Additional portions of DMSO (0.1mL) and oxetan-3-amine (7.14 μl, 0.103 mmol) were added to the reactionmixture which was stirred for an additional 15 h at 23° C. The reactionmixture was diluted with water (0.8 mL) and the crude product wasextracted with EtOAc (2.0 mL). The organic layer was separated, washedwith brine (1 mL), dried over Na2SO4, filtered, rinsed with EtOAc, anddried in vacuo. The crude material was purified by flash columnchromatography using a gradient of 10-100% EtOAc in heptane to providethe free base of the title compound (9.1 mg, 41.6% yield) as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51 (br. s., 3H), 2.63 (t, J=4.6Hz, 4H), 3.43 (br. s., 4H), 3.60 (s, 2H), 4.62 (t, J=6.3 Hz, 2H), 4.82(t, J=6.8 Hz, 2H), 4.91-5.02 (m, 1H), 7.09 (td, J=8.5, 2.4 Hz, 1H), 7.23(td, J=9.9, 2.7 Hz, 1H), 7.32 (s, 1H), 7.38 (d, J=4.9 Hz, 1H), 7.46-7.54(m, 1H), 8.64 (s, 1H); ESI-MS: m/z (M+H)+ 427.0.

The compounds of the invention can be administered alone or in the formof a pharmaceutical composition. In practice, the compounds of theinvention are usually administered in the form of pharmaceuticalcompositions, that is, in admixture with at least one pharmaceuticallyacceptable excipient. The proportion and nature of any pharmaceuticallyacceptable excipient(s) are determined by the properties of the selectedcompound of the invention, the chosen route of administration, andstandard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising: a compound of invention and at least onepharmaceutically acceptable excipient.

In effecting treatment of a patient in need of such treatment, acompound of the invention can be administered in any form and routewhich makes the compound bioavailable. The compounds of the inventioncan be administered by a variety of routes, including orally, inparticularly by tablets and capsules. The compounds of the invention canbe administered parenteral routes, more particularly by inhalation,subcutaneously, intramuscularly, intravenously, intraarterially,transdermally, intranasally, rectally, vaginally, occularly, topically,sublingually, and buccally, intraperitoneally, intraadiposally,intrathecally and via local delivery for example by catheter or stent.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances. Thepharmaceutical compositions of the invention may be administered to thepatient, for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 50% of theweight of the unit dose form. The term “pharmaceutically acceptableexcipient” refers to those typically used in preparing pharmaceuticalcompositions and should be pharmaceutically pure and non-toxic in theamounts used. They generally are a solid, semi-solid, or liquid materialwhich in the aggregate can serve as a vehicle or medium for the activeingredient. Some examples of pharmaceutically acceptable excipients arefound in Remington's Pharmaceutical Sciences and the Handbook ofPharmaceutical Excipients and include diluents, vehicles, carriers,ointment bases, binders, disintegrates, lubricants, glidants, sweeteningagents, flavoring agents, gel bases, sustained release matrices,stabilizing agents, preservatives, solvents, suspending agents, buffers,emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in aunit dose form, each dose typically containing from about 0.5 mg toabout 100 mg of a compounds of the invention. The term “unit dose form”refers to a physically discrete unit containing a predetermined quantityof active ingredient, in association with a suitable pharmaceuticalexcipient, by which one or more is used throughout the dosing regimen toproduce the desired therapeutic effect. One or more “unit dose form” maybe taken to affect the treatment dosage on a daily schedule.

In one particular variation, the composition is a pharmaceuticalcomposition adapted for oral administration, such as a tablet or acapsule or a liquid formulation, for example, a solution or suspension,adapted for oral administration. In still another particular variation,the pharmaceutical composition is a liquid formulation adapted forparenteral administration.

Compounds of the present invention are modulators of GPR6, and as suchare useful in the treatment and prevention of conditions associated withGPR6. As mentioned above, the major striatal targets of dopaminergicinnervation reside in the medium spiny neurons (MSNs) of thestriatopallidal (indirect) and striatonigral (direct) output pathways.The MSNs of the direct output pathway express D1 dopamine receptorswhereas those in the indirect pathway express D2 receptors. GPR6 isenriched in D2 receptor expressing MSNs in the striatum where GPR6activity is functionally opposed to D2 receptor signaling. Antagonism orinverse agonism of Gs coupled GPR6 decreases cAMP in MSNs and provides afunctional alternative to dopamine mediated activation of D2 receptors.

Antagonism or inverse agonism of Gs coupled GPR6 provides a functionalalternative to dopamine mediated activation of D2 receptors. As such,compounds that modulate the activity of GPR6 are useful for treating ina variety of neurological and psychiatric disorders. For examplemovement disorders including Parkinson's disease and Huntington'sdisease either alone or in combination with other agents are approvedfor the treatment of Parkinson's disease including L-DOPA, dopaminergicagonists, MAO B inhibitors, DOPA decarboxylase inhibitors and C(O)MTinhibitors. Other disease indications that could be treated bymodulation of GPR6 include drug addiction and eating disorders,cognitive disorders, schizophrenia, bipolar disorders, and depression.

In another embodiment, the invention provides methods of treatingconditions associated with GPR6, comprising: administering to a patientin need thereof an effective amount of a compound of the invention. Inanother embodiment, a compound of the invention is provided for use as amedicament. The invention also provides the use of a compound of theinvention, including the use for the manufacture of a medicament, totreat the conditions associated with GPR6 described herein. Thecompounds of the present invention are useful as GPR6 modulators for avariety of subjects (e.g., humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate toany unhealthy or abnormal state. The term “conditions associated withGPR6” includes conditions, disorders, and diseases in which themodulators of GPR6 provides a therapeutic benefit, such as Parkinson'sdisease, levodopa induced dyskinesias, and Huntington's disease, drugaddiction, eating disorders, cognitive disorders, schizophrenia, bipolardisorders, and depression.

The terms “treat,” “treatment,” and “treating” include improvement ofthe conditions described herein. The terms “treat,” “treatment,” and“treating” include all processes providing slowing, interrupting,arresting, controlling, or stopping of the state or progression of theconditions described herein, but does not necessarily indicate a totalelimination of all symptoms or a cure of the condition. The terms“treat,” “treatment,” and “treating” are intended to include therapeutictreatment of such disorders. The terms “treat,” “treatment,” and“treating” are intended to include prophylactic treatment of suchdisorders.

As used herein the terms “patient” and “subject” includes humans andnon-human animals, for example, mammals, such as mice, rats, guineapigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. Theterm also includes birds, fish, reptiles, amphibians, and the like. Itis understood that a more particular patient is a human. Also, moreparticular patients and subjects are non-human mammals, such as mice,rats, and dogs.

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the mentioned condition. Aneffective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto, the species of patient, its size, age, and general health; thespecific condition, disorder, or disease involved; the degree of orinvolvement or the severity of the condition, disorder, or disease, theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present invention, thetreatment dosage, is expected to range from 1 mg to 200 mg. Specificamounts can be determined by the skilled person. Although these dosagesare based on an average human subject having a mass of about 60 kg toabout 70 kg, the physician will be able to determine the appropriatedose for other patients.

The pathological hallmark of Parkinson disease (PD) is neuronal cellloss within the substantia nigra. Degeneration of the nigrostriatalpathway causes reduction in the striatal concentration of dopamine whichresults in motor and nonmotor clinical manifestations. Many Parkinson'sdisease patients are treated with levodopa, a prodrug for dopamine.Levodopa has common serious side effects including induced dyskinesia(LID), impulsive control disorders (ICD), psychotic symptoms and sleepdisturbances. LID is progressive (90% of PD patients develop LID within10yrs). Irreversible adaptations occur in D1 receptor signaling in MSNsin rodent models of LID including reduced desensitization leading tohypersensitivity in the direct pathway. Genetic inactivation of D1 butnot D2 receptors abolishes LID in mice. However blockade of D1 receptorsignaling does not affect the antiparkinsonian efficacy of L-DOPA.

In a particular embodiment, the present invention provides a method oftreating Parkinson's disease comprising: administering to a patient inneed thereof an effective amount of a compound of the invention. Thatis, the invention also provides the use of a compound of the invention,including the use for the manufacture of a medicament, to treatParkinson's disease.

The compounds of the invention may be combined with one or more otherpharmacologically active compounds or therapies for the treatment of oneor more disorders, diseases or conditions for which GPR6 is indicatedmay be administered simultaneously, sequentially or separately incombination with one or more compounds or therapies for treatingParkinson's disease, levodopa induced dyskinesias, and Huntington'sdisease, drug addiction, eating disorders, cognitive disorders,schizophrenia, bipolar disorders, and depression. Such combinations mayoffer significant therapeutic advantages, including fewer side effects,improved ability to treat underserved patient populations, orsynergistic activity. In particular, the compounds of the invention maybe administered with levodopa for treating Parkinson's disease. Thepresent invention provides a method treating Parkinson's diseasecomprising: administering to a patient in need thereof an effectiveamount of a compound of the invention in combination with levadopa. Theinvention also provides the use of a compound of the invention incombination with levadopa, including the use for the manufacture of amedicament, to treat Parkinson's disease.

The activity of compounds as GPR6 modulators may be determined by avariety of methods, including in vitro and in vivo methods.

EXAMPLE A

Inhibition of cAMP activity of GPR6 in vitro assay

This cell based assay measures the ability of compounds to inhibit theconstitutive cAMP activity of GPR6 receptor expressed in CHO-K1 cells.CHO cells were stably expressed with GPR6 receptor, whose expression iscontrolled by a tetracycline inducable element. The cells were culturedin medium containing F12K, 10% FBS, 1% Penn/Strep, 200 ug/mL Hygromycin.GPR6 receptor expression was induced for 20 hrs with 2 □g/ml doxycycline(sigma D9891) in growth media. After addition of doxycycline cells wereplated at a density of 450-750 cells per well in 96-well half-volumeblack tissue culture plates (Costar) and placed in an incubator (37°, 5%CO2) for 20 hours prior to cAMP assays.

Culture media was removed from cells and they were washed with 50□L/well of Ringer's Buffer (MgCl2 0.047 mg/mL, NaH2PO4 0.18 mg/mL,Na2HPO4 0.1 mg/mL, KCl 0.34 mg/mL, NaHCO3 1.26 mg/mL, D-glucose 1.8mg/mL, NaCl 7 mg/mL; pH=7.4). Compounds suspended in DMSO were dilutedin Ringer's Buffer containing 0.5% fatty acid free BSA plus 300 μM IBMXand incubated on cells for 45 min at 37° and 5% CO2. After incubationcells were incubated for 10 min at room temp with Eu-cAMP tracersolution from a Perkin Elmer Lance HTRF Ultra cAMP assay kit (TRF0263).Then ULight™-anti-cAMP solution from the Lance HTRF kit was added andincubated on a shaker at room temp for 1 hour prior to HTRF detection ina Perkin Elmer Envision plate reader.

IC50 curves were generated with a four-parameter logistic equation usingGraphPad Prism 5.03. Measured EC50 value (nM) of example compounds inthis assay is provided in the Table 1 below.

TABLE 1 Ex. EC50 (nM) 1 59.4 2 16.5 3 88.2 4 49.6 5 30.1 7 6 47.9 8 18.59 52.3 10 69.3 11 61.4 12 49.4 13 48.2 14 75.2 15 21.9 16 17 18 39.9 1962.6 20 81.4 21 162.2 22 37.3 23 158.1 24 311.2 25 277.8 26 466.2 27446.3 28 >1000 29 >1000 30 80.1 31 188 32 326 33 101.7 34 94.9 35 66.436 76.3 37 128 38 309 39 >5000 40 >1000 41 >1000 42 275.6 43 >100044 >1000 45 >1000 46 >1000 47 >1000 48 >1000 49 >1000 50 163.7

EXAMPLE B

Haloperidol-Induced Catalepsy—In Vivo Rodent Parkinson's Disease Model

The motor symptoms of Parkinson's disease include akinesia,bradykinesia, rigidity, tremor and postural abnormalities and areassociated with the loss of nigral dopaminergic cells and a decline instriatal dopamine levels. Administration of haloperidol to rodents leadsto a transient parkinsonian-like state that is reversed by theadministration of L-Dopa (Duty, S.; Jenner, P. Br. J. Pharmacol. (2011),164, 1357-1391) and other drugs that have been clinically validated forthe treatment of Parkinson's disease. Haloperidol antagonizes dopamineD2 and, to a lesser extent, D1 receptors in medium spiny neurons thatcomprise the indirect and direct pathways of the motor circuitrespectively. The resultant block of striatal dopamine transmissionresults in abnormal downstream firing within the basal ganglia circuitsthat is manifest as symptoms of muscle rigidity and catalepsy. Catalepsyhas been postulated to reflect the clinical features of Parkinson'sdisease, whereby patients experience an inability of to initiatemovements.

Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200g are used. Alternatively, male C57Bl6 mice weighing 25-35 g were used.The cataleptic state was induced by the subcutaneous administration ofthe dopamine receptor antagonist haloperidol (0.3 mg/kg, sc), 90 minbefore testing the animals on the vertical grid test. For this test, therats or mice were placed on the wire mesh cover of a 25 cm×43 cmplexiglass cage placed at an angle of about 70 degrees with the benchtable. The subject was placed on the grid with all four legs abductedand extended (“frog posture”). The use of such an unnatural posture isessential for the specificity of this test for catalepsy. The time spanfrom placement of the paws until the first complete removal of one paw(descent latency) was measured maximally for 120 sec for rats. For mice,the front paws of a mouse was placed on a horizontal metal bar raised 2″above a Plexiglas platform and time was recorded for up to 30 secondsper trial. The test ended when the animal's front paws returned to theplatform or after 30 seconds. The test was repeated three times and theaverage of the three trials was reported as the intensity index ofcatalepsy.

Catalepsy was measured 30 min, 90 min, and/or 90 min after dosing thesubjects a 1.0 mg/kg i.p. dose of haloperidol along with the GPR6modulator test compound. Test compound plasma and brain levels weredetermined by collected tissue samples at the end of the experiment,which was either at the 120 or 240 min time point. A representativenumber of compounds of the invention were administered in a dose rangefrom 0.1 to 100 mg/kg i.p, sc or po in conjunction with haloperidol. TheA2a antagonist KW6002 (istradefylline) was dosed at 0.6 mg/kg i.p. as apositive control.

Measured % reversal of example compounds in this assay is provided inthe Table 2 below.

TABLE 2 Ex. Species Dose (mg/kg) Route % reversal at 90 min 7 Rat 1 sc33.5 7 Rat 10 sc 63.6 7 Rat 30 sc 42.8 *significantly different thanvehicle contol, one-way ANOVA with Bonferroni's multiple testcorrection.

1. The compound of formula I

or a pharmaceutically acceptable salt thereof, wherein R₁ is selectedfrom the group consisting of optionally substituted C₃₋₈ cycloalkyl,optionally substituted C₃₋₆ heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionally substituted C₁₋₁₀ heteroaryl; X₁ is N and X₂ is CH;or X₁ is CH and X₂ is N; or X₁ is N and X₂ is N; when X₁ is N, Z isselected from the group consisting of C₁₋₆ alkylene, C₁₋₆ haloalkylene,—C(O)—, and —S(O)₂—; when X₁ is CH, Z is selected from the groupconsisting of C₁₋₆ alkylene, C₁₋₆ haloalkylene, —O—, —C(O)—, —NH—, —S—,—S(O)—, and —S(O)₂—; q is 0, 1, or 2; s is 0, 1, or 2; R₂ is —OR₅ or—NR₆R₇; R₃, each time taken, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and trifluoromethyl; p is 0,1, or 2; R₄, each time taken, is independently selected from the groupconsisting of C₁₋₆ alkyl, hydroxy, and halo; r is 0 or 1; R₅ is selectedfrom the group consisting of C₁₋₆ alkyl and C₃₋₈ cycloalkyl; R₆ isselected from the group consisting of hydrogen and C₁₋₆ alkyl; R₇ isselected from the group consisting of optionally substituted C₁₋₆ alkyl,C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted C₃₋₆heterocyclyl; X₃ is CCH₃ and X₄ is N; or X₃ is N and X₄ is CCH₃;excluding the compounds:N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;3-(4-(5-chloro-2-fluorobenzyl)piperazin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-2-(4-(2,4-difluorobenzyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;(1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)(2,5-difluorophenyl)methanone;N-cyclopropyl-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(S)-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;3-(4-(4-chloro-2-fluorophenoxy)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)-4-fluoropyridin-2(1H)-one;(R)-N-cyclopropyl-3-(4-((2,5-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(R)-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(S)-N-cyclopropyl-3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;3-(4-((5-chloro-2-fluorophenyl)difluoromethyl)piperidin-1-yl)-N-cyclopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;5-chloro-1-((1-(2-(cyclopropylamino)-7-methylpyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methyl)pyridin-2(1H)-one;N-cyclopropyl-3-(4-((2,5-difluorophenyl)difluoromethyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-((4-fluorophenyl)sulfonyl)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;andN-cyclopropyl-3-(1-(2,4-difluorobenzyl)piperidin-4-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine.2. The compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein X₁ is CH and X₂ is N.
 3. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinX₁ is N and X₂ is N.
 4. The compound or pharmaceutically acceptable saltthereof according to claim 3 wherein X₃ is CCH₃ and X₄ is N.
 5. Thecompound or pharmaceutically acceptable salt thereof according to claim1 wherein R₁ is optionally substituted C₆₋₁₀ aryl.
 6. The compound orpharmaceutically acceptable salt thereof according to claim 1, wherein Zis C₁₋₆ alkylene.
 7. The compound or pharmaceutically acceptable saltthereof according to claim 1, wherein Z is —O—.
 8. The compound orpharmaceutically acceptable salt thereof according to claim 1, wherein Zis —C(O)—.
 9. The compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein R₂ NR₆R₇.
 10. The compound according toclaim 1, which is selected from the group consisting of:3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;(S)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(S)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(R)-3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(1,3-cis)-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;(1,3-cis)-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-((1,3-trans)-3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine;3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-((1,3-trans)-3-fluorocyclobutyl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(1,3-trans)-3-((3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;(1,3-trans)-3-((3-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-yl)amino)cyclobutanol;3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine;3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-2-amine;3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(R)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(S)-3-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(R)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(S)-3-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-2-amine;N-cyclopropyl-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-2-amine;(R)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;(S)-3-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-2-amine;2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;(R)-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;(R)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;(R)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-(4-(difluoromethoxy)-2-fluorophenoxy)piperidin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;(R)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-(2-fluoro-4-methoxybenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-N-isopropyl-7-methylpyrido[3,4-b]pyrazin-3-amine;N-cyclopropyl-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methylpyrido[3,4-b]pyrazin-3-amine;(R)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;(S)-2-(4-(4-(difluoromethoxy)-2-fluorobenzyl)piperazin-1-yl)-7-methyl-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine;and2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-7-methyl-N-(oxetan-3-yl)pyrido[3,4-b]pyrazin-3-amine;or a pharmaceutically acceptable salt of any one of the above-mentionedcompounds.
 11. A pharmaceutical composition comprising a compound orpharmaceutically acceptable salt thereof as defined in claim 1, and apharmaceutically acceptable excipient.
 12. A method of treating adisease, disorder or condition in a subject, the method comprisingadministering to the subject a compound or pharmaceutically acceptablesalt thereof as defined in claim 1, wherein the disease, disorder orcondition is selected from Parkinson's disease, levodopa induceddyskinesias, Huntington's disease, drug addiction, eating disorders,cognitive disorders, schizophrenia, bipolar disorders, and depression.